10 γδ T cell effector functions_ a blend of innate programming and acquired plasticity

8/2/2019 10 T cell effector functions_ a blend of innate programming and acquired plasticity

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Th intgrit f highr rtbrats is maintaind thrghprtcti mchanisms that can dtct strss-indcddtrminants that aris fing infctin, inr r c-ar atratins. This srianc ins bth innatand adapti immn prcsss. Innat rspnss, mainmdiatd b natra kir (NK) cs and mmn-ctic cs, ar radi actiatd fing ngagmntf nn-cna rcptrs rfrrd t as pattern recognitionreceptor (PRRs), hich ar spcific fr dtrminantsthat ar brad xprssd b micrrganisms r arprgatd b hst cs in rspns t c strss1,2. PRRngagmnt triggrs an infammatr rspns that ini-tia ads t incrasd micrbicida and cttxic fnc-tins f immn cs, and caranc f th iciting agnt,and atr t tiss rpair and immn dnmdatin3.Adapti immn cs ha ra fnctins that ar sim-iar t ths f innat cs bt, ing t immngicammr, th can id strngr and fastr rspnss

aftr rpatd xpsr t a gin iciting agnt4. Thstabishmnt f immngica mmr impis xpan-sin f T and B cs, spcific fr th iciting antign,aftr ngagmnt f cna distribtd T c rcptrs(TCRs) and B c rcptrs (BCRs). Cna xpanddT and B c ppatins acqir a rstrictd st f ffctrfnctins that ar prsmab bst sitd fr caranc fth iciting agnt at a gin tim pint in a gin tis-s. Innat cs ar ind in th indctin f adaptiimmn rspnss f apprpriat strngth, kintics andfnctin in t as. First, th fficint intrnaizpathgns and ding cs and prcss thm int pp-tid antigns that ar prsntd in th cntxt f MHC

mcs t conventional T cell. Scnd, th intgratdangr and infammatr cs and transat thm intstimi that ad t prpr fnctina parizatin f T c and B c rspnss4.

Athgh, gnra, innat immn rspnss pr-cd adapti immn rspnss, a rrs intrpafrm adapti t innat immn ffctrs as cntrib-ts t th ar rcritmnt and actiatin f innatimmn cs and sbsqnt fnctina parizatinf MHC-rstrictd T cs. T cs cntribting t thisrrs crsstak in sbsts f T cs rstrictdb th nn-pmrphic MHC cass I-ik mcsCD1d and MHC-ratd prtin 1 (MR1) (knn asinvariant NKT cell and mucoa-aociated invariant T cell,rspcti), as as T cs xprssing TCRs 5,6.Ths mphcts ha bn trmd nn-cnntina,innat-ik r transitina T cs, ing t sra dis-tingishing fatrs that ar shard ith innat immn

cs5,7. Simiar t thr nn-cnntina T cs, T cs rcgniz cnsrd nn-pptid antigns thatar prgatd b strssd cs, th xprssin mdai-tis and distribtin f hich rsmb ths fpathogen-aociated molecular pattern (PAMPs) r danger-aociatedmolecular pattern (DAMPs) rcgnizd b PRRs. Thscs acqir a pr-actiatd phntp assciatd ith thprgatin f mmr markrs ar in thir dp-mnt. This pr-actiatd stats as rapid indctin fffctr fnctins fing th dtctin f tiss strss.Anthr imprtant fatr f T cs is thir trpismfr pithia srfacs, sch as ths f th ir and skin,and mcsa frm rspiratr, digsti and rprdcti

*Institut National de la Sant

et de la Recherche Mdicale(INSERM) U892, IRT UN,

8 quai Moncousu, BP 70721,

44007 Nantes cedex 1,

France.Integrated Department of

Immunology, National Jewish

Health and University of

Colorado, Denver,

Colorado 80206, USA.

Correspondence to M.B. or

W.K.B.

emails: bonnevil@nantes.

inserm.fr;[email protected]

doi:10.1038/nri2781

Publihed online 11 June 2010

Pattern recognition receptor

(PRR). A hot receptor (uch a

Toll-like receptor (TLR) or

NOD-like receptor (NLR))

that can ene pathogen-

aociated molecular patternand initiate ignalling cacade

that lead to an innate immune

repone. Thee can be

membrane bound (uch a

TLR) or oluble cytoplamic

receptor (uch a retinoic

acid-inducible gene I (RIG-I),

melanoma differentiation-

aociated gene 5 (MDA5)

and NLR).

T cell effector functions: a blendof innate programming and acquiredplasticityMarc Bonneville*, Rebecca L. OBrien and Willi K. Born

Abstract | T cells have several innate cell-like features that allow their early activation

following recognition of conserved stress-induced ligands. Here we review recent

observations revealing the ability of T cells to rapidly produce cytokines that regulatepathogen clearance, inflammation and tissue homeostasis in response to tissue stress. These

studies provide insights into how they acquire these properties, through both developmental

programming in the thymus and functional polarization in the periphery. Innate features of

T cells underlie their non-redundant role in several physiopathological contexts and are

therefore being exploited in the design of new immunotherapeutic approaches.

REVIEWS

NATuRe RevIewS |Immunology voluMe 10 | july 2010 |467

20 Macmillan Publishers Limited. All rights reserved10
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Conventional T cell

A T cell ubet pecific for

peptide antigen that are

preented by polymorphic

MHC cla I molecule (HLA-A,

HLA-B, HLA-C in human,

H2K, H2D, H2L in mice)

or MHC cla II molecule

(HLA-DP, HLA-DQ, HLA-DR in

human, IE or IA in mice).

rgans, t hr th migrat ar in thir dpmntand prsist as rsidnt cs. Intrsting, th frqntxprss inariant r cs ratd TCRs in a gintiss sit, hich diffr frm n tiss t anthr, rfct-ing hmgns, bt distinct, antign rcgnitin rpr-tirs frm n tiss t anthr (BOX 1). Th phsigicars ffid b T cs ar arid and incd pr-tcti immnit against xtracar and intracarpathgns, tmr srianc, mdatin f innat andadapti immn rspnss, tiss haing and pithiac maintnanc, and rgatin f phsigica rganfnctin5,7. Thir cntribtin t man f ths phsi-pathgica prcsss has bn rad b anasis fmic dficint fr indiida T c sbsts.

As sggstd b rcnt bsratins that ar ridhr, th nn-rdndant r f T cs in arisphsipathgica prcsss ris n a cmbinatinf antign spcificit, tiss distribtin and fnctinaprprtis rathr than n an f ths indiida.Ths stdis prid n insight int th crdinatdacqisitin f a rstrictd st f TCRs, tiss hming and

ffctr fnctins ar dring T c dpmntthat gi ris t T c rspnss ith apprpriatkintic, spatia and fnctina charactristics. In addi-tin t this innat prgramming, spciaizd sbsts f

T cs rtain fnctina pasticit in th priphr,hich as thm t xrt distinct ffctr fnctinsdpnding n th infammatr cntxt and th rcp-trs that ar ngagd. Hr prps mchanismsxpaining h T c fnctina spciaizatin andpasticit accnt fr thir intrpa ith immn andnn-immn partnr cs. Imprd ndrstanding fsch car intrpas has bn rcnt xpitd inth dsign f innati immnthraptic apprachstargting T cs in hmans.

Activation and functional attributes of T cellsTh xpansin and fnctina diffrntiatin f MHC-rstrictd T cs rqirs cncmitant ngagmntf th TCR and c-stimatr rcptrs that fnctintgthr t gnrat signas f apprpriat strngth, dra-tin and qait. DAMPs ar snsd b c-stimatrrcptrs, th ngagmnt f hich dtrmins hthra nai T c prcrsr i xpand and diffrntiat intffctr cs. In th cas f T cs, th dtctin fstrss-indcd mcs is achid b bth TCR and

nn-TCR mcs (sch as T-ik rcptrs (TlRs)and natural killer receptor (NKRs)) that act sparat,snrgistica r additi t actiat particar T cffctr fnctins (FIG. 1).

Sensing of cell stress and infection through TCRs. wkn itt abt th spcificit and antign rcgnitinmdaitis f TCRs. As rcnt rid8, sra ig-ands that intract ith TCRs ar MHC mcs rMHC-ratd mcs (sch as th ms T10 and T22mcs r th hman CD1c mcs). TCRs asbind t MHC-nratd mcs, sch as ira gc-prtins9 r htrmric ATPas cmpxs10. Binding tths MHC-nratd mcs might rfct frtitscrssractiit f TCRs that as bind MHC-ratdmcs r phsigica rcgnitin f htr gnsdtrminants, as sggstd b th nsa immn-gbin-ik antign rcgnitin md f TCRs shnb rcnt strctra stdis11. Irrspcti f th xactspcificit f TCRs, a f thir igands dscribd s farar markd prgatd in rspns t car infctinr dsrgatin. This DAMP-ik charactristic is assming shard b thr t ndfind TCR igands.Fr xamp, binding stdis sing rcmbinant TCRsdrid frm ms inariant v6v1+ and v1v6.3+T cs indicat rapid prgatin f thir rspcti ig-ands n pritna macrphags fing infctin ith

Listeria monocytogenes and prgatin f v6v1 TCRigands fing TlR signaing12. An intrsting xam-p f rcgnitin f bth strss-indcd mcs andPAMPs is pridd b hman v9v2+ T cs, hichar actiatd b isprnid patha mtabits knnas phsphantigns1315. Hman v9v2+ T cs can bactiatd b r sma amnts (


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Stress-induced NKRligands, such as RAE1,MICA, MICB and ULBPs

Stress-induced TCR ligandssuch as CD1c, T10 and T22Microbial and endogenousphosphoantigens

Target cell

DAMPsandPAMPs

TLR

NKG2D

Cytotoxicity

Proliferation,cytokine release,immunoregulation

and cytoprotection

Inflammation(IL-17 and IFN)

Dectin 1

TCR

T cell

Inflammation,DNA damage,oncogenesis

and infections

Invariant NKT cell

(iNKT cell). Lymphocyte that

expre a particular variable

gene egment, V14 (in mice)

and V24 (in human),

preciely rearranged to a

particular J gene egment to

yield T cell receptor -chain

with an invariant equence.

Typically, thee cell expre

memory T cell marker and

NK cell receptor, are enriched

in the liver, are activated by

recognition of CD1d

(particularly when bound with

-galactoylceramide) and

readily produce IL-2, IL-4,

IL-13 and IFN.

Mucosa-associated

invariant T cell

(MAIT cell). A conerved

mammalian T cell ubetexpreing TCR -chain with

a canonical V7.2 junctional

equence in rodent and

human. MAIT cell are pecific

for an a yet undefined antigen

that i bound to the

monomorphic MHC

cla I-related MR1 product.

similar to iNKT cell, MAIT cell

frequently expre memory

T cell marker and NK cell

receptor, but differ from

iNKT cell by their tropim for

intetinal rather than liver

tiue.

amnts f micrbia phsphantigns and prntsthm frm bing actiatd b nrma tiss cs thatxprss basa s f th ak stimatr mam-maian mtabits. whn mammaian cs ar acti-

atd r ndrg transfrmatin, phsphantigns arhigh prgatd t s that ar sfficint t actiatv9v2+ T cs, spprting thir r in th rcgni-tin f bth c strss and infctin. Th mdaitisf phsphantign-mdiatd stimatin f hmanv9v2+ T cs rmain nknn bt pssib inc srfac rcptrs ith knn affinit fr phsphr-atd sbstrats, sch as th rcnt idntifid ct-F1ATP snthas cmpx10. Da rcgnitin f strss andinfctin is as achid b hman v1+ T cs, asman f thm ract in a TCR-dpndnt mannr againstbth pithia c-drid tmrs and cs infctd bcmmn hrpsirss16.

Sensing of cell stress and infection through other recep-

tors.Th dtctin f strss b T cs as ins

nn-cna rcptrs, sch as TlRs and NKRs, that arprgatd fing fnctina diffrntiatin f mm-r T cs.As rcnt rid17, T c rspnsst tmr and infctd cs ar fin-tnd b actiat-ing and inhibitr immngbin-ik r ctin-ikNKRs. Th actiating rcptr natural killer group 2,member D (NKG2D) has a k r in ths prcsssing t its brad xprssin b T cs and its rac-tiit against cnsrd MHC-ratd igands that arprgatd b transfrmd r infctd cs18. NKG2Dgnra fnctins snrgistica ith th TCR as a c-stimatr19,20, bt it can as triggr cttxic rspnssb intrapidrma ms v5v1+ T cs against

pithia tmrs21 r b hman v9v2+ T csagainst irs-infctd targts22 itht cncmitantTCR ngagmnt. Th mchanisms ndring TCR-dpndnt rss TCR-indpndnt NKG2D actiatinar sti ncar, bt th prbab dpnd n th tisscntxt f T c actiatin and th dgr f prirxpsr f th cs t infammatr ctkins23.

In additin t NKRs, th ngagmnt f TlRs andNOD-like receptor b PAMPs triggrs ar infam-matr rspnss mdiatd b innat cs and nn-cnntina T cs, incding T cs. In particar,intractins btn xtracar bactria and PRRs(sch as TlR2 and dctin 1 (as knn as CleC7A))xprssd b ms v6v1+ cs prbab cntrib-t t thir ar actiatin in intrapritna infctinmds24,25. Mr cmmn, actiatin f T crspnss b PAMPs is indirct, ining TlR-indcdras f pr-infammatr ctkins b dndritic cs(DCs). Simiar t NK cs and inariant NKT cs2628,sch indirct actiatin, hich can b achid ith ritht cncmitant ngagmnt f th TCR r NKRs,

ads t ar indctin f intrfrn- (IFN) prdctinthrgh a psiti fdback p ining intrkin-12(Il-12)29,30r tp I IFNs31. PAMPs can as indircttriggr Il-17 prdctin b ms v6v1+ T cs,thrgh th indctin f Il-23 prdctin b DCs aftrc-ngagmnt f TlR2 and NlRs24,25.

Activation kinetics. Th rapid actiatin f T csccrs ing t qaitati and qantitati fatrs.Sra T c sbsts ha a mmr and pr-actiatd phntp in nai indiidas, ithr as acnsqnc f intrathmic dpmnta prgram-ming (s atr) r pstnata priphra stimatin bnirnmnta r strss-indcd igands (fr xamp,in th cas f hman v9v2+ T cs32). Mrr,th high frqnc f pr-xisting T cs that canrspnd t a gin chang as nabs rspnsst ccr rapid, itht th nd fr prir sctinand xpansin. In this rgard, intractins btn TCRs and strss-indcd igands in rcrrntgrmin mtifs that ar shard b a arg fractin fnn-sctd TCRs8, hich, in th cas f rcgnitinf T10 r T22 b ms T cs, cntribt t mst fth igandTCR binding nrg33. This mchanismbpasss th nd fr ampificatin f mphctsith th rant spcificit thrgh thmic sctinr priphra antign-drin prcsss. Fina, th

xprssin f diffrnt hming rcptrs b dping thmcts ith distinct TCR rprtirs frthrnhancs th frqnc f T cs ith a gin anti-gn spcificit in a gin tiss and nabs thir rapidactiatin in rspns t c strss.

Effector functions. T cs ha a brad arra f ffctrfnctins that rfct thir inmnt in dirs phsi-pathgica prcsss. Th can ki infctd, actiatdr transfrmd cs, thrgh pathas that in thngagmnt f dath-indcing rcptrs, sch as CD95(as knn as FAS) and TNF-ratd apptsis-indcingigand rcptrs (TRAIlR), and th ras f cttxic

Figure 1 | Sesi f cear stress ad ifecti b T ces. T cells canrecognize separately, additively or synergistically three sets of stress-induced stimuli:

MHC-related and -unrelated T cell receptor (TCR) ligands (such as the weakly

polymorphic MHC class I-like human CD1c molecules and mouse T10 and T22 molecules,

and microbial and endogenous phosphoantigens), various cell surface molecules (such as

retinoic acid early transcript 1 (RAE1) and MHC class I polypeptide-related sequence A

(MICA)) that engage the activating natural killer receptors (NKRs) such as NK group 2,

member D (NKG2D), and/or danger-associated molecular patterns (DAMPs) or

pathogen-associated molecular patterns (PAMPs) recognized by pattern recognition

receptors (such as Toll-like receptors (TLRs) and dectin 1). IFN, interferon-; IL-17,interleukin-17; ULBP, cytomegalovirus UL16-binding protein.

R E V I E W S


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Pathogen-associatedmolecular pattern

(PAMP). Conerved motif

recognized by PRR that are

broadly expreed by variou

clae of microorganim

but abent from mammal.

Example include lipoteichoic

acid (in Gram-poitive

bacteria), lipoarabinomannan

(in mycobacteria), dextran

(in fungi), lipopolyaccharide

(in Gram-negative bacteria),

double-tranded RNA (in

virue) and CpG DNA

(in bacteria).

Danger-associated

molecular pattern

(DAMP). A conerved

mammalian motif, recognized

by PRR, that i broadly

upregulated in repone to

cellular tre. Example

include heat hock protein,

high motility group box 1

protein (HMGB1), DNA-bending

protein and uric acid.

Natural killer receptors

(NKR). Receptor initially

identified on NK cell and later

hown to be expreed by

ome memory T cell a well.

NKR are either related to

immunoglobulin (uch a

killer immunoglobulin-like

receptor (KIR) or to C-type

lectin (uch a NKRP1 or

CD94NKG2). some NKR

(uch a the KIRS gene

product) deliver activating

ignal wherea other (uch

a the MHC cla I-pecific

KIRLlgene product) deliver

inhibitory ignal.

Natural killer group 2,

member D

(NKG2D). An activatinglectin-like receptor expreed

by mot NK cell, CD8+

T cell and T cell. NKG2D

i pecific for different MHC

cla I-related ligand that may

be upregulated on activated,

tranformed or viru-infected

cell, uch a member of the

retinoic acid early trancript 1

(RAE1) and cytomegaloviru

UL16-binding protein (ULBP)

familie in rodent and human,

or the MHC cla polypeptide-

related equence A (MICA) and

MICB in human.

ffctr mcs, sch as prfrin and granzms22,34.Mrr, th cntribt t pathgn caranc dirctthrgh th prdctin f bactristatic r tic m-cs, sch as gransin and dfnsins34,35, and indirctthrgh th indctin f antibactria fnctins f thrimmn ffctr cs and pithia cs36. T cscan prdc immnmdatr ctkins that arind in prtcti immnit against irss andintracar pathgns (tmr ncrsis factr (TNF)and IFN), xtracar bactria and fngi (Il-17), andxtracar parasits (Il-4, Il-5 and Il-13). Thsctkin rspnss as ndri th bnficia r d-tris r f T cs dring ndgns strss-indcd immn prcsss, sch as tmr-indcdinfammatin (thrgh prdctin f IFN, Il-6 andgranctmacrphag cn-stimating factr(GM-CSF)), atimmnit (thrgh prdctin fIFN and Il-17), and arg and asthma (thrghprdctin f Il-4 and Il-13). Fina, T cs candnmdat innat and adapti immn ffctr csthrgh th prdctin f immnspprssi ctkins

(transfrming grth factr- (TGF) and Il-10), andprmt tiss haing and pithia c rgnratinthrgh th prdctin f pithia c grth factrs(kratinct grth factr 1 (KGF1; as knn asFGF7) and KGF2 (as knn as FGF10)) and sriafactrs (eGF1; as knn as fibrpin 1) (fr rcntris, s REFs 37,38).

T cell programming and plasticity

Nn f th fatrs dscribd in th pris sctinis niq t T cs, as th ar shard ith innatimmn cs (fr xamp, fnctins in antibact-ria dfnc and tiss rpair), T cs (fr xamp,ctkin rspnss) and thr innat-ik T cs (frxamp, rapid actiatin kintics and c strss rcgni-tin). Hr, th fnctina spciaizatin f T csbsts bsts thm ith a niq abiit t carr t arstrictd st f tasks ith spatia and tmpra fatrsthat ar nmatchd b thr immn ffctrs.

Functional specialization. As a ppatin, T cscan carr t man dirs fnctins, bt indiidasbsts ithin th ppatin ha mr rstrictd ffc-tr prprtis, dpnding n thir xprssd TCRs, thirtiss catin and thir actiatin stats (TABLE 1). Frxamp, bth ms v5v1+ intrapidrma T csand v7+ intstina pithia mphcts (Iels) sh

nhancd ctprtcti, immnmdatr andantibactria fnctins fing pithia c inrand/r tmrignsis, and this is assciatd ith thprdctin f pithia c trphic factrs (sch asKGFs, eGFs and insin-ik grth factr 1 (IGF1)),infammatr ctkins (sch as Il-2 and IFN) andnhancd cttxic actiit37. B cntrast, msv6v1+ T cs main prdc Il-17 dring pm-nar infammatin39, ms v1v6.3+ T cs prdcIl-4 and IFN in th ir40, and ms v4+ T cs pr-dc IFN r Il-17 dpnding n th md stdid4143.Thr sms t b a simiar fnctina spciaizatin fhman T cs: hman v2+ T cs gnra ha

high cttxic actiit and prdc high s f IFNand TNF, hras hman v1+ T cs ha r ct-txic ptntia and prdc a bradr st f ctkins,incding Il-4 and Il-17 (REFs 44,45).

Thr ar simiaritis and diffrncs in th fnc-tina spciaizatin f ffctr T cs and T cs(BOX 2). Simiar t cttxic CD8+ T cs, IFN prdc-tin b T cs is rgatd b th transcriptin fac-trs T-bt and msdrmin46, simiar t T

H2 cs and

tp 2 CD8+ T cs, Il-4 prdctin b T cs cr-rats ith GATA-binding prtin 3 (GATA3) xprs-sin47 and, simiar t T

H17 cs, Il-17 prdctin b

T cs is cntrd b rtinic acid rcptr-ratdrphan rcptr-t (RoRt)45,48. Frthrmr, simiar tcassica MHC-rstrictd T cs, fnctina pariza-tin in T cs is assciatd ith th xprssin fdistinct chmkin rcptrs, sch as CC-chmkinrcptr 5 (CCR5) xprssin b T

H1-ik T cs49

and CCR6 fr Il-17-prdcing T cs45,50. Hr,thr ar sm imprtant diffrncs btn th fnc-tina spciaizatin f cnntina T cs and

T cs: th fnctina spciaizatin f T csftn crrats ith th xprssin f particar TCR

ariab (v) gns38, th acqisitin f rgatr fnc-tins b T cs ma nt rqir th transcriptin fac-tr frkhad bx P3 (FoXP3) (athgh hman FoXP3+ T cs cd b indcd in vitro51) and th prdc-tin f ctkins sch as Il-5 and Il-13 b T csis indcd b Il-4 bt ths ctkins ar prdcd bhman T cs in rspns t Il-2 (REF. 52).

Developmental programming. Th fnctina spciai-zatin f T cs rsts frm bth dpmntaprgramming and pasticit in th priphr. w sth trm prgramming t rfr t th crdinatdacqisitin f a rstrictd TCR rprtir, tiss-hmingcapabiitis and ffctr fnctins dring intrathmicdpmnt that is, bfr th first ncntr ithan iciting agnt in th priphr. Pasticit rfrs t thindctin ithin a gin T c sbst in th priph-r f spcific fnctins frm a argr st f ptntiaactiitis, dpnding n its actiatin cntxt.

Dpmnta prgramming accnts fr th hm-gns TCR rprtir, rstrictd tiss catin anddistinct fnctina prprtis f ms T c sbstsxprssing inariant TCRs (FIG. 2). Prgrammd rar-rangmnts f distinct sts f TCR v, dirsit (D) and

ining (j) sgmnts at diffrnt tim pints f fta th-

ms dpmnt and a ack f trmina dxncti-dtransfras (an nzm rqird fr TCR nctinadirsificatin) in fta T c prcrsrs far thprdctin f TCRs ith th apprpriat cannica

nctina sqncs and ndri th gnratin f dis-tinct tmpra as f thmcts xprssing diffrntinariant TCRs dring fta dpmnt 53. SctiTCR ngagmnts and thir tmpra and car cn-txt dring intrathmic dpmnt prbab dtrminth st f chmkin rcptrs xprssd and th fnc-tina prprtis f a gin T c sbst. Fr xam-p, ngagmnt f th inariant ms v5v1 TCR ndping thmcts b thmic pithia cs triggrs

R E V I E W S

470 | july 2010 | voluMe 10 www.atre.c/reviews/i

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5/12

NOD-like receptors

(NLR). A family of cytoplamic

PRR that trigger immune

repone againt microbial

threat. For example, NLRP3

ene microbial ligand,

endogenou danger ignal

and certain crytalline

ubtance, and it initiate

the aembly of the NLRP3

inflammaome. 22 human and

34 moue NLR gene have

been identified.

th xprssin f skin hming rcptrs and TH1-ik

ffctr c fnctins, aing ar sding f th pi-

drmis b this particar T c sbst 54,55, hich is s-a rfrrd t as th dndritic pidrma T c (DeTC)sbst. F matratin f DeTCs ins intrathmicand priphra intractins ith sctin and pkp fintrapithia T cs 1 (SKINT1), an immngbinsprfami mmbr that is xprssd b thmic pithiacs and kratincts56. B cntrast, th abiit t hm tth ir r spn, t prgat th c-rcptr CD4 andt prdc Il-4, Il-13 r IFN is crdinat acqirdb ms thmcts xprssing cannica v1v6.3TCRs. Simiar t iNKT cs, fnctina prgramming fv1v6.3 T cs is cntrd b th transcriptin factrprmctic kamia zinc-fingr (PlZF; as knn

as ZBTB16)57,58. In vitro TCR crssinking xprimnts58and anasis f mic ith gntica atrd TCR signa-

ing47,57,5961 indicat a r fr TCR ngagmnt in PlZFprgatin. Mrr, dpmnta prgramming fv1v6.3+ T cs ins th ngagmnt f signaingmphctic actiatin mc (SlAM) fami rcptrsb thmic hamatpitic cs and sbsqnt SlAM-assciatd prtin (SAP) signaing in th dping T cs, simiar t dping iNKT cs57. Fina,rcnt stdis sggst that igatin f TCR and/r CD27n crtain thmcts ads t th acqisitin f innatT

H1 c-ik prprtis, hras fair t stabish sch

intractins ads t th gnratin f thmcts thatar prn t prdc Il-17, ing t prgatin (r ss-taind xprssin) f RoRt62,63. Athgh ths stdis

Table 1 |Functional roles of mouse T cell subsets

T ce sbset lcati Effectr fctis (prraedi te ts r idcibe i teperiper)

Re i disease r ijr Refs

V V

V1 ND Lymphoid tissue Programmed: TNF and IFN

Inducible: TH2-type cytokines and IL-17

Resolves lung inflammation 78

Inhibits virus-induced myocarditis 135

Promotes non-specific AHR 136,137Inhibits T

Regcell development 96

Promotes CGD 65

V5 Thymus andspleen

Programmed: cytokines are unknownbut IL-4 and IL-13 are not produced

Promotes AHR 72,138

Promotes IgE responses 73

V6.3 andV6.4

Thymus, spleenand liver

Programmed: IFN, IL-4, IL-13 andcytotoxicity

iNKT cell-like properties 40

Kills macrophages in vitro 81

V4 ND Lymphoid tissueand lung

Programmed: IL-17

Inducible: TNF, IFN and cytotoxicity

Promotes viral myocarditis and killsvirus-infected myocytes

135

Promotes virus-induced lung inflammation 139

Promotes virus-induced encephalitis 140

Inhibits subcutaneous melanoma *

Inhibits AHR 71,72

Promotes innate bacterial clearance 36

Selected V4 Lymph node Inducible: IL-17 Exacerbates CIA 43

V5 Spleen Inducible: IFN-dependent development Suppresses IgE responses 73

V5 V1 invariant Epidermis Programmed: IL-22, IFN, TNF, KGF1,IGF1, CCL5, defensins, MIP1, XCL1 andcytotoxicity

Promotes tissue repair and wound healing 37,110

Protects against skin carcinogenesis 21

Suppresses GVHD 141

V4 and others Mammary gland ND Tissue remodelling (lactating mammarygland)?

116

V6 V1 invariant Tongue, uterus,placenta, testes,

lung and kidney

Programmed: IL-17, IL-22, IFN, TGFand cytotoxicity

Tissue remodelling (placenta)? 115

Inhibits nephritis 142

Prevents lung fibrosis 39

Promotes innate bacterial clearance 24

V7 V4 and others Intestinal mucosa Programmed: TNF, IFN, KGF1 andcytotoxicity

Protects intestinal barrier function 106,108

Promotes epithelial cell turnover 103

Prevents colitis 105,107

AHR, airway hyperresponsiveness; CCL, CC-chemokine ligand; CIA, collagen-induced arthritis; CGD, chronic granulomatous disease; GVHD, graft-versus-hostdisease; IGF1, insulin-like growth factor 1; IL, interleukin; IFN, interferon-; iNKT, invariant natural killer T; KGF1, keratinocyte growth factor 1; MIP1, macrophageinflammatory protein 1; ND, not determined; TGF, transforming growth factor-; T

H, T helper; TNF, tumour necrosis factor; T

Reg, regulatory T; XCL1, XC-chemokine

ligand 1. *Z. Yin, personal communication.

R E V I E W S


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6/12

Chronic granulomatous

disease

(CGD). A human primary

immunodeficiency yndrome

aociated with

hyperinflammation and

increaed uceptibility to

bacterial and fungal infection.

Allergic airway

hyperresponsiveness

(Allergic AHR; alo known a

bronchial hyperreponive-

ne). A tate characterized byeaily triggered bronchopam

(contraction of the mall

airway). AHR i a hallmark

of athma, and it occur

frequently in individual with

chronic obtructive pulmonary

dieae. It can be induced in

mice by allergen enitization

and challenge or by airway

expoure to environmental

trigger uch a ozone.

Bronchial challenge with

nonpecific agent uch a

methacholine or hitamine i

ued a a tet for AHR.

d nt r t th pssibiit that TCR intractins ithas t nidntifid igands cntribt t T

H17-ik

T c prgramming, th sggst that th markd TH17-

ik parizatin f th inariant v6v1+ c sbstcd rst frm ack f intrathmic ngagmnt f itsTCR dring fta dpmnt48. Irrspcti f this iss,it has rcnt bn rprtd that additina signas (schas TGF) in th thms r aftr thms xit ha a kr in th cmmitmnt f nsctd thmcts tbcm cs ith th abiit t prdc Il-17 (REF. 64).

Functional plasticity. T cs ha t kinds f fnc-tina pasticit, hich trm acqird pasticit andinnat pasticit. Acqird pasticit rfrs t th ng-asting abiit f a gin T c t xrt diffrnt sts fc-rgatd ffctr prprtis in rspns t TCR sig-naing and particar nirnmnta cs. This prcss,shn b th diffrntiatin f nai T cs int T

H1 r

TH2 cs fing priming b irss r xtracar

parasits, rspcti, as th gnratin f mmrT cs ith fnctina attribts that ar bst sitdfr th rapid iminatin f th iciting agnt dringrca infctins. B cntrast, innat pasticit rfrs tth cntxt-dpndnt actiatin f a particar ffc-tr fnctin itht ng-trm fnctina imprinting.

As tind b, bth acqird and innat pasticitcntribt t T c fnctina spciaizatin.

In cntrast t th prgrammd Il-17 prdctin bms v6v1+ T cs, v4+ T cs in th mphidtisss ha n inhrnt dpmnta bias tards Il-17prdctin. Hr, th acqir sch parizatin rtim in a md f cagn-indcd arthritis, accmpa-nid b antign-drin TCR sctin43. Sch acqirdpasticit might as xpain th strng Il-17 rspnsf ms v1+ cs in chronic granulomatou dieae65, asthis sbst prdcs T

H1- and T

H2-tp ctkins in thr

sttings. Th dichtm f ms v1v6.3+ T cs,hich incd bth T

H0-ik CD4+NK1.1 and T

H1-ik

CD4NK1.1+ ppatins47, might as rfct thir abi-it t diffrntiat int diffrnt ffctr tps, dpnd-ing n th cntxt f priphra actiatin, a hpthsisthat is cnsistnt ith th bsrd nrichmnt f CD4

NK1.1+v1v6.3+ cs in priphra hpatspnic ca-tins40,47,59. Th prfrntia T

H1 c-ik parizatin f

hman v9v2+ T cs, charactrizd b ptnt TNFand IFN prdctin and cttxic rspnss17,44, isprbab acqird dring thir pstnata priphraxpansin b nirnmnta antigns32. Nrthss,this sbst can sti b parizd in vitro int csith fatrs assciatd ith T

H2 cs, T

H17 cs, f-

icar T hpr cs r rgatr T cs, dpndingn th ctkins pridd tgthr ith th TCRstimi51,52,66,67. Th phsipathgica ranc f thisacqird pasticit is spprtd b th bsratin frciprca atratins f T

H1 c-ik and T

H2 c-ik

fnctins f T c sbsts in patints ith HIv infc-tin68, and th crratin btn a diatin fex vivohman v9v2+ T c rspnss t a T

H2 c-tp and

impaird cntr f mcbactria infctins69.

with rspct t innat pasticit, th diffrntia indc-tin f particar ffctr fnctins ma dpnd n thcass f innat rcptr that is ngagd, th natr fth infammatr stimi and th strngth f th TCRsigna. Fr xamp, NKG2D signaing triggrs cttxicfnctins f hman v9v2+ T cs, thrb infnc-ing sis r sria f th targt c, bt it has mr im-itd ffcts n ctkin rspnss70. Il-12 r tp I IFNsrasd b stimatd mmnctic cs in rspnst TlR3 and TlR4 ngagmnt triggr amst xcsiIFN prdctin b hman v9v2+ T cs31. Simiar,T c-drid Il-21 transint prgats granzm Bprdctin b hman v9v2+ T cs, bt n has a im-itd ffct n thir ctkin rspnss67.Th DC-mdiatdpriphra indctin f ms v4+ T cs that sp-prss allergic airway hyperreponivene (AHR) is ctkindpndnt, transint, antign indpndnt and nt ass-ciatd ith priphra TCR sctin71,72, and it thrfrsms t b basd n th innat pasticit f ths T cs. Innat pasticit might simiar accnt fr thppatins f T cs in th spn that psiti rngati rgat Ige rspnss73.v1+ T cs arprsnt in th spns f nrma mic and prmt pri-mar Ige rspnss t intrapritna inctin f a-bmin (ovA) in am, hras spnic v4+ T csthat spprss an Ige rspns ar indcd b rpatd air-a chang ith ovA, hich at th sam tim ads t

ss f th Ige-prmting fnctins f th v1+ T cs.Ths xamps sh th imitatins t fnctina pastic-it: athgh ach sbst, infncd b xtrna stimi,might chang its fnctin cnsidrab, thr sms t bn rap in fnctina ffcts btn sbsts.

Cellular interplay in health and disease

Interplay with innate cells. Th rapid ras b rsidnt T cs f ptnt chmattractants fr ntrphis andmacrphags in rspns t tiss strss cntribts tth ar rcritmnt f sra innat immn ffctrs(FIG. 3a). In this rspct, T cs r rcnt shnt b th primar srcs f th ntrphi-attracting

Box 2 | Functional subsets of T cells

CD4+ T helper (TH) and CD8+ cytotoxic (T

C) cells can be subdivided into functional

subsets or lineages, with distinct and heritable functional profiles (reviewed in REFs

132134). TH1 and T

C1 cells contribute to inflammatory responses against intracellular

pathogens and tumours, and they mainly produce interferon (IFN), which is underthe control of the transcriptional regulator Tbet (and eomesodermin in the case of

TC1 cells), induced by signalling through the interleukin12 receptor (IL12R). T

H2 and

TC2 cells contribute to immune defence against extracellular parasites and providehelp for IgG1 and IgE class switching. They produce IL4, IL5 and IL13 under the

control of the transcriptional regulator GATAbinding protein 3 (GATA3), induced by

signalling through IL25R. TH17 and T

C17 cells contribute to immune defence against

fungi and extracellular bacteria, notably through neutrophil recruitment and

activation. They produce IL17A, IL17F, IL21 and IL22 under the control of the

transcriptional regulator retinoic acid receptorrelated orphan receptort (RORt),induced by signalling through IL6R and IL21R. Additional functional subsets have

been described, which nevertheless might not fulfill all the criteria of a bona fide

functional lineage, owing to their heterogeneity or functional plasticity. This is the

case for regulatory T cells which downregulate systemic T cell responses and

provide help for IgA class switching through the production of transforming growth

factor (under the control of the transcriptional regulator forkhead box P3) andfollicular T helper cells, which have unique B cell follicle homing features and potent

antibody production helper activity.

R E V I E W S


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7/12

Fetalprecursor

T-bet+ EOMES+

T-bet+EOMES+

V5V1 TCR

V1V6.3 TCR

V6V1 TCR

CD122

IL-22, IFNand TNF

CCR10V5 TCR

V1

TEC

SKINT1

Thymus

Epidermis

Programmed TCRrearrangements

Intrathymicfunctionalprogramming

Peripheral homingand activation

V6

V1TGF

Uterine, vaginal,tongue and lung

epithelia

IL-23R

RORt+

AHR

CCR6

IL-17, IL-22,IFN and TGF

RORt+

V6.3

Thymic cell ofhaematopoietic origin

V1Liver and spleen

PLZF+

SLAMF

SAP1

NK1.1

CD4(+/)

IL-4, IL-13and IFN

PLZF+

T-bet+

Il-17 in ms mds f infctin24, hprsnsitiit39and atimmnit43. As rcnt rprtd, th high f Il-17 prdctin b T cs in particar ca-tins, sch as th pritnm, sms t dpnd argn prir indctin r xpansin f Il-17-prdcing

T c sbsts in rspns t cmmnsa bactria74.Hman T cs as prdc Il-17 and, in patintsith acti pmnar tbrcsis, th can cnstittmst f th Il-17+ cs75. Il-17 prdctin is rstrictdt crtain tps f ithr innat (v6v1+) r acqird(v4+) c sbsts in mic, hich ar actiatd at arr at stags f th immn rspns, rspcti.Innat and acqird Il-17+ T cs as diffr in thirfnctina ptntia n innat Il-17+ T csrtain th abiit t prdc IFN and ar indcibb ctkins an, hras acqird Il-17+ T csar indcd b TCR signaing tgthr ith T

H17 c-

parizing ctkins and in thir inmnt in th

aris disas prcsss48. Fr xamp, ar Il-17prdctin b ms v6v1+ T cs dring infc-tin and spsis is indcd b Il-23 sming ithtcncmitant TCR ngagmnt, hras TCR signasmight b rqird fr Il-17 prdctin b T cs

in stri infammatin48. Th bsratin f impairdntrphiic rspnss and bactria caranc in TCR-chain-dficint mic indicats a crcia and bnficiar fr ar Il-17 prdctin b T cs in thsprcsss76. Cnsistnt ith this, ar Il-17 prdc-tin b innat ms v6v1+ T cs inhibits ngfibrsis in a md f bactria-indcd hprsnsitiitpnmnitis39 and bmcin-indcd ng inr77.

Hr, Il-17-prdcing T cs can as bpathgnic in sra immn-mdiatd disass. In par-ticar, dptin f ms v4+ T cs that mdiat anantign-drin Il-17 rspns dring cagn-indcdarthritis rdcs disas incidnc and srit43.

Figure 2 | Fctia prrai f ivariat r ivariat-ie T ce sbsets. Through programmedrearrangements, fetal precursors generate successive waves of T cells expressing V5V1, V1V6.3 or V6V1 T cellreceptors (TCRs) with invariant or highly related junctional sequences. SKINT1 (selection and upkeep of intraepithelial

T cells 1)-dependent interactions between invariant mouse V5V1+ T cells and thymic epithelial cells (TECs) induceearly commitment to a T helper 1 (T

H1) cell-like phenotype and the acquisition of receptors that promote homing to the

skin (CC-chemokine receptor 10 (CCR10)). Exit from the thymus depends on sphingosine 1-phosphate receptor 1

(S1PR1). V5V1+ thymocytes then migrate to the epidermis where they acquire their typical dendritic morphology.SLAM-associated protein 1 (SAP1)-dependent interactions between V1V6.3+ T cells and thymic cells of haematopoieticorigin, presumably in conjunction with TCR engagement, upregulate expression of the transcription factor promyelocytic

leukaemia zinc-finger (PLZF) and subsequent upregulation of CD4 and natural killer 1.1 (NK1.1) and production of

interleukin-4 (IL-4), IL-13 and interferon- (IFN), which are under the control of the transcription factors PLZF and T-bet.Lack of TCR engagement by thymocytes expressing invariant V6V1 TCRs presumably leads to a transforming growthfactor- (TGF)-dependent default pathway associated with acquisition of T

H17 cell-like properties, under the control of

the transcription factor retinoic acid receptor-related orphan receptor-t (RORt), and the ability to home to uterine,vaginal, tongue and lung epithelia. AHR, aryl hydrocarbon receptor;EOMES, eomesodermin; R, receptor; SLAMF,

signalling lymphocytic activation molecule F; TNF, tumour necrosis factor.

R E V I E W S




8/12

a Early: innate boost b Intermediate: adaptive boost c Late: downmodulation of immune responsesand tissue repair

Mature DCImmature DC

Proliferationandpolarization

Proliferationand polarization

Maturation

Trophicfactors

Tissue repair

Activatedmacrophage

B cell

Epithelium

Programmed T cells

Programmed orpolarized T cells

Polarized T cells

Neutrophil

Neutrophil

IL-17 CCL2

Monocyte ormacrophage

Monocyte ormacrophage

T cell

T cell

B cellactivation

T cellactivation RecruitmentKilling Killing

andsuppression

Innate cellrecruitmentand activation

Stress detectionand T cellactivation

Mic dfcti fr indamin 2,3-dixgnas (IDo),an nzm ind in th catabism f trptphan,spntans dp a chrnic granmats dis-as-ik sndrm. Ths mic dp a strng Il-17rspns mdiatd b acqird v1+ T cs tgthrith nhancd ntrphiic infitratin t th ngs andsbsqnt act ng inr, hich cd b ami-ratd b ntraizatin f Il-17 r T c dptin65.

Th actiatin f T cs in mic fing car-anc f infnza irs infctin sggsts a r fr T cs in th rstin f th innat infammatrrspnss78. Ths at T c rspnss cntribtin a nn-rdndant mannr t th dnmdatinf infctin-indcd infammatin, as indicatd bth argr and ngr-asting infammatr sins inTCR -chain-dficint mic than id-tp mic cha-ngd ith intracar bactria79. This ffct might b

xpaind in part b nhancd macrphag rcritmnt80bt as b T c-mdiatd kiing f actiatd macr-phags81, pssib thrgh rcgnitin f cnsrd ig-ands that ar prgatd dring infammatin12 (FIG. 3c).Innat-ik v6v1+ T cs sm t b rspnsib frth initia rcritmnt f macrphags, hras th sb-sqnt phas f macrphag sis dpnds n acqirdv4+ and v1+ T cs78.

Interplay with antigen-presenting cells and conventionalT cells. DCs ar ptnt indcrs f T c ffctrfnctins ing t thir abiit t xprss igands fr TCRs and NKRs and t prid c-stimatin signas

that snrgiz and smtims bpass TCR ngagmnt(FIGs 3b, 4). Fr xamp, DCs stimat mr TNF andIFN prdctin b phsphantign-stimatd hmanv9v2+ T cs than thr tps f antign-prsntingc (APC)29. Mrr, aftr TlR3 r TlR4 ngagmnt,DCs ras Il-12 r tp I IFNs that indc IFN pr-dctin b hman v9v2+ T cs in a TCR-indpndntmannr31. Simiar, in ms mds f arthritis andbrain ischamiarprfsin inr82,83, DCs actiatdthrgh igatin f TlR2 r NoD rcptrs bcm aptnt src f Il-23 that spprts Il-17 prdctin b T cs. Fina, in a ms md f AHR, adptitransfrrd CD8+ DCs spprtd th indctin f msv4+ T cs that spprss AHR72. In this intrpa, dirctcntact btn T cs and spnic CD8+ DCs smst b ssntia. In trn, intractins btn T csand DCs indc DC actiatin and diffrntiatin b s-

ra mchanisms (FIG. 3b). Fr xamp, IFN prdcdb phsphantign-stimatd hman v9v2+ T csnhancs, thrgh an IFN- and Il-12-mdiatd psi-ti fdback p, Il-12 prdctin b DCs, hich canthn prmt th dpmnt f T

H1-tp T cs29.

Hman v9v2+ T cs simiar indc rapid diffr-ntiatin f mncts int infammatr DCs, hichcan triggr, ndr th infnc f frthr micrbiastimi, parizd dpmnt f T cs xprssing IFNr Il-17 (REF. 84). Fina, in a ms md f itisindcd b immnizatin ith an atantignic pptid,Il-17-prdcing T cs cd dirct prmt thdpmnt f thr Il-17-prdcing T cs85.

Figure 3 | Cear iterpa ivvi T ces. a | Early boosting of innate responses. Following sensing of stress

signals on epithelial cells or dendritic cells (DCs), tissue-resident T cells with programmed effector functions promotethe recruitment and activation of innate cells (such as neutrophils through interleukin-17 (IL-17) production, or

monocytes and macrophages through CC-chemokine ligand 2 (CCL2) production). b | Intermediate boosting of adaptive

immune responses. Crosstalk between T cells and DCs leads on the one hand to proliferation and functionalpolarization of T cells and on the other hand to maturation of immature DCs. Both programmed and polarized T cells modulate functional polarization of T cells together with mature DCs and promote B cell responses and antibody

class switching. c | Late downmodulation of immune responses and tissue repair. T cells downmodulate inflammationand immune effectors through cytotoxicity and immunosuppressive cytokines. They also contribute to tissue repair

through local release of epithelial cell growth and survival factors and recruitment of innate effector cells.

R E V I E W S




9/12

Antign-stimatd hman v9v2+ T cs rrcnt shn t dispa sra hamarks f prfs-sina APCs, sch as prgatin f MHC cass I andcass II mcs and f th c-stimatr mcsCD40 and CD83, abiit t phagcts and prcss anti-gn, and abiit t actiat nai T cs8688. Athghths fatrs might as app t sm ms T cs89,s far a f ths bsratins ha bn mad frm std-is in vitro. It rmains t b dtrmind hn and hrAPC fnctins f T cs might ha a r in vivo, andhthr th APC fnctin is indd a niq attribt f T cs cmpard ith thr T c sbsts.

T cs can as ngati rgat T c actiatinand infammatin dring infctins, tmrs and at-immn prcsss (FIG. 3c). Th inhibitr mchanismsind ar arid and incd accratd pathgn car-anc ing t nhancd rcritmnt f innat cs, dirctiminatin f actiatd macrphags, DCs r T cs81,9092and prdctin f ctkins (sch as TGF and Il-10)that spprss T c-dpndnt infammatin91,92.Athgh ths prcsss might inhibit pathgnic T c

rspnss in atimmn sitatins93,94, th can b d-tris if th targt tmr-spcific T cs (fr xam-p, in hman brast and prstat cancrs)95 r rgatrT cs (fr xamp, in ms AHR mds)96.

Interplay with B cells. Th rigina bsratin that T c-dficint mic sti dpd nrma grmi-na cntrs and cass-sitchd antibdis sggstd that T cs might b ab t prid hp in ths prcsssinstad f T cs97. Cnsistnt ith this hpthsis, T c hp fr B cs cd b indcd in a parasiticinfctin in th absnc f thr T cs98. Cmpardith id-tp mic, T c-dficint mic shddcrasd s f ovA-spcific Ige and IgG1 antibd-is in th bd aftr intrapritna immnizatin ithovA, hich r rstrd ith administratin f Il-4,impicating T cs as a prbab src f this crciactkin99. B cntrast, rpatd aira chang f micith ovA indcd spnic T cs that cd spprssth primar Ige rspns t this antign100. As mntindarir, ths ppsing Ige rgatr ffcts ar mdiatdb diffrnt T cs: spntans dping v1+T cs incding th v1v5+ sbst nhanc Igerspnss, hras indcib (acqird) v4+ T csspprss th T c-dpndnt antign-spcific Igerspnss73. Accrding in a md f mcbactriainfctin, T c-dpndnt grmina cntr frmatin

and Ige prdctin r inkd t CD4+ Il-4-prdcing T cs and rgatd thrgh CD5-mdiatd inhibi-tin101. In hmans, inmnt f v9v2+ T cs inB c hp is spprtd b thir abiit t prdc B cc-stimatr mcs (sch as CD40 igand, CD70and indcib T c c-stimatr (ICoS)) and thirprsnc in gastrintstina mphid tisss, in cstrsithin grmina cntrs f B c fics102. Cnsistntith this, Il-21 indcs in vitro acqisitin f ficarT hpr c fatrs b hman v9v2+ T cs, sch as amphid hming phntp and high- xprssin fth ficar B c-attracting chmkin CXC-chmkinigand 13 (CXCl13)52.

Interplay with non-immune cells. Th distinct tiss tr-pism f T cs and cs cntacts ith pithia andndthia cs impis inmnt in crsstak ithnn-immn cs (FIGs 3a,c). Accrding, dcrasdtrnr f intstina pithia cs in TCR -chain-dficint mic sggstd that T cs can prmt pi-thia c hmstasis103. In t ms mds f isatrph and hprtrph, KGF1 xprssin as highstin th intstina crpts and rstrictd t Iels104. Inadditin, citis indcd in id-tp mic b adminis-tratin f dxtran sdim sphat r haptns as assci-atd ith infitratin f KGF1-prdcing Iels in thinfamd mcsa and, if indcd in TCR-dficint mic,as assciatd ith dad pithia c rcr105107. Iels xprss sm f th nctina mcs thathd pithia cs tgthr, incding e-cadhrin (asknn as cadhrin 1) and ccdin, th xprssin fhich is incrasd b TCR stimatin108. This fatrmight b imprtant fr T cs t sstain pithiabarrir fnctin109.

In th skin, intrapidrma ms v5v1+ DeTCs,hich rcgniz strssd kratincts, cntribt t pi-thia c hmstasis thrgh th prdctin f ari-

s diffrnt factrs, incding KGFs and IGF1 (REF. 37).DeTCs bcm actiatd in skin nds thrghTCR stimatin110, and th ras KGFs that triggrharnan prdctin b nighbring kratincts111and sbsqnt rcritmnt f macrphags that pr-mt nd rpair. Simiar t thir ms cntrparts,hman skin-infitrating v1+ T cs isatd frm actnds prdc IGF1 and cntribt t accratdnd csr in in vitro mds112. Ms T cs ascntribt t pithia c rpair aftr crna pithiac abrasin113 and aftr ng xpsr t zn r b-mcin114. T cs frm inrd ngs rapid prdcIl-17, hich prmts th rcritmnt f ntrphis76,

Figure 4 | T cededritic ce iteractis i a ra

se . A V4+ T cell (red), which might havearrived in the lung through a nearby blood vessel (green),

is observed interacting with an MHC class II-expressing

pulmonary dendritic cell (DC; blue). At any one moment,

~50% of the T cells in the normal adult C57BL/6 mouselung can be seen making such contacts, suggesting a

continuous monitoring of the more frequent DCs by

relatively few T cells. The inset shows high-level T cellreceptor (TCR) staining at the interface between the

T cell and DC, which might indicate engagement of

the TCRs during this cellular interaction. Image fromJ. M. Wands (National Jewish Health, Denver, Colorado, USA).

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http://www.uniprot.org/uniprot/P12830http://www.uniprot.org/uniprot/Q16625http://www.uniprot.org/uniprot/Q16625http://www.uniprot.org/uniprot/P12830


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Antibody-dependent cell

cytotoxicity

(ADCC). A cytotoxic

mechanim mediated by

engagement of low-affinity

receptor for the contant

fragment of IgG (FcRIII; alo

known a CD16) by

antibody-coated target cell.

hich in trn prmt accratd rna f th airapithim77. Fina, transint T c xpansins in thpacnta115 and actating mammar gands116 sggst thirinmnt in th rmding f ths rapid changingpithia c tisss.

Clinical implications

Th stdis in mic ha pridd imprtant cs t thphsigica rs f T cs (TABLE 1), bt ing tth diffrncs btn ms and hman T c sb-sts xamind s far, ths stdis ha nt gnra pr-dictd th bhair f hman T cs. Nrthss,cmparisn f fnctina anags sbsts in bthspcis can bring insight int hman T c immn-big. Fr xamp, mdaitis f nd haingb ctans hman v1+ T cs can b indirctaddrssd thrgh anasis f ms v5v1+ DeTCs,as bth sbsts can prdc pithia c grth factrsin rspns t tiss inr110113. Simiar, ms irv1v6.3+ T cs id a T c mphprifrati dis-as in mtant mic ith atrd TCR signaing60 that

shs simiaritis ith hman hpatspnic T cmphmas117. Thrfr, anasis f ms v1v6.3+T c fnctins might prid insights int th atigf this rar hman npastic disas.

Immnthrapis targting hman v9v2+ T csha bn rcnt dpd, taking adantag f thhigh frqnc and brad antitmr and antimicr-bia prprtis f this sbst118. Aaiab cinica-gradcmpnds act ithr dirct t actiat v9v2+ T cs(sch as th snthtic phsphantigns brmhdrinprphsphat (Phsphstim; Innat Pharma) andcHDMAPP (Picstim; Innat Pharma) r indc intra-car accmatin f hman v9v2+ T c agnists(sch as th aminbisphsphnats pamidrnat (Ardia;Nartis) and zdrnat (Zmta/Zmra/Acasta/Rcast; Nartis))118. Bth tps f mc ha bntstd in primats t assss th in vivo cnsqnc fv9v2+ T c actiatin in hath and disas119 andr shn t indc accratd pathgn carancand rpair f infamd tisss aftr Yersiniapestis infc-tin120. Basd n ths prcina data, Phas I and II cini-ca trias r rcnt carrid t in patints ith cancrsand chrnic ira infctins121,122. C-administratin fhman v9v2+ T c agnists and Il-2 in ths patintsindcd fficint in vivo actiatin and xpansin f T cs ith imitd adrs nts. Mrr, in vivov9v2+ T c ampificatin aftr tratmnt crratd

ith disas stabiizatin r partia tmr rgrssin inpatints ith mtip mma r hrmn-rsistantmtastatic prstat carcinmas121,122. In a rcnt Phas IIcinica tria, phsphantign tratmnt as indcd arapid dcras in hpatitis C ira ads in 50% f chrni-ca infctd patints, prsmab thrgh prmtin f T c-mdiatd IFN rspnss123. Fina, th abiitf hman v9v2+ T cs t ki tmr cs thrghantibody-dependent cell cytotoxicity124 as xpitd ina cinica tria cmbining a B c mphma-spcificmncna antibd (ritximab (Ritxan/Mabthra;Gnntch/Rch/Bign Idc)) and phsphantignsps Il-2 in patints ith ficar B c mphma

rapsing aftr antibd tratmnt. Priminar findingssggst a highr cmpt cinica rspns rat thanxpctd frm grps tratd ith ritximab an inpris stdis125. If cnfirmd, sch rsts d ar-rant a mr frma assssmnt f th risk/bnfit rati fsch a cmbinatin apprach in argr patint chrts.

Concluding remarks

Dspit rcnt prgrss in th ndrstanding f strsssnsing b T cs, th strctra fatrs and rcgni-tin mdaitis f mst TCR igands rmain nknn,and th qstin f hthr T cs rcgniz strc-tra ratd mcs rmains pn. Addrssing thisqstin shd prid imprtant cs abt th c-tin f TCRs and thir igands, and th ph-gntic prssr xrtd n particar T c sbstsith sming mandatr fnctins. Mrr, char-actrizatin f antigns rcgnizd b TCRs shdimpr r ndrstanding f th rgatin f T csb infammatr and strss signas and th mchanismscntring th distinct tmpra ngagmnt f T c

sbsts in th crs f disas. Frthrmr, th finmdaitis f fnctina diffrntiatin f dping T cs and actiatin f thir ffctr fnctins asrmain si. Dtaid ndrstanding f ths prc-sss i rqir cidatin f at ast fr k isss:first, h transcriptin factrs assciatd ith ithrT

H1 c-ik fnctina prgramms (that is, T-bt) r

TH0 c-ik fnctina prgramms (that is, PlZF)

ar diffrntia indcd in psiti sctd th-mcts. Scnd, hthr TCR signas ar rqirdfr intrathmic sctin, fnctina prgramming rpriphra actiatin f innat T

H17 c-ik T c

sbsts, sch as th inariant ms v6v1+ sbst.Third, if TCR signas ar nt rqird, hat might bth mchanisms ndring th gnratin f inariantms v6v1 TCRs ith nctina sqncs that aridntica t ths f psiti sctd inariant msv5v1 TCRs and, fina, hat nn-TCR signas arind in th ar r at fnctina cmmitmnt finnat and acqird T c sbsts.

Frm a cinica pint f i, n ntab drabackf crrnt immnthrapis targting hman v9v2+T cs is th rapid xhastin f prifratin and ffc-tr rspnss b ths cs aftr rpatd tratmntsith phsphantigns r aminbisphsphnats118. Thndring mchanisms f this phnmnn rmainnknn, bt cd rfct in vivo stimatin f ths

cs in a sbptima car cntxt. Dtaid char-actrizatin f anrgic T cs indcd b rpatdphsphantign r aminbisphsphnat tratmntsand f th factrs rqird fr sstaind actiatin andng trm sria f T cs i prbab b rqirdt s this k iss. Fina thr T c sbsts(v2) ar as prmising immnthraptic targtsagainst infctins and tmrs, as th gnrat strngrspnss against mcbactria126, hrpsirss127 andsid tmrs16. Car, charactrizatin f th antignrcgnizd b ths v2 T cs rmains a prrqisitfr thraptic xpitatin f thir brad antimicrbiaand antitmr prprtis.

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AcknowledgementsWe thank H. Sicard (Innate Pharma, Marseilles, France) for help-ful suggestions, Z. Yin (Yale School of Medicine, New Haven,

Connecticut, USA) for personal communication and J. M. Wands(NJH, Denver, Colorado, USA) for the image used in figure 4.

Competing interests statement.The authors declare competing financial interests: See Webversion for details.

DATABASESUniProtKB:http://www.uniprot.org

CD1c|CD1d|CD95|dectin 1 | E-cadherin|EGF1|GM-CSF |

granzyme B|IFN|IGF1|IL-4|IL-5|IL-6 |IL-10|IL-13|IL-17|KGF1| KGF2|MR1| occludin| PLZF | SKINT1 | TLR2 | TLR3|

TLR4 | TNF

FURTHER INFORMATIONMarc Bonnevilles homepage:www.crcna.univ-nantes.fr/

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10 γδ T cell effector functions_ a blend of innate programming and acquired plasticity

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