of April 19, 2018.This information is current as

T Cell Functions in the MouseδγAnalysis of

and Rebecca L. O'BrienWilli K. Born, Zhinan Yin, Youn-Soo Hahn, Deming Sun

http://www.jimmunol.org/content/184/8/4055doi: 10.4049/jimmunol.0903679

2010; 184:4055-4061; ;J Immunol 

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Analysis of gd T Cell Functions in the MouseWilli K. Born,*,† Zhinan Yin,‡ Youn-Soo Hahn,x Deming Sun,{ and Rebecca L. O’Brien*,†

Mouse models of disease and injury have been invaluablein investigations of the functional role of gd T cells. Theyshow that gd T cells engage in immune responses bothearly and late, that they can function both polyclonallyand as peripherally selected clones, and that they can beeffector cells and immune regulators. They also suggestthat functional development of gd T cells occurs step-wise in thymus and periphery, and that it is governed bygd TCR-signaling and other signals. Finally, they indi-cate that gd T cell functions often segregate with TCR-defined subsets, in contrast to conventional T cells.From the functional studies in mice and other animalmodels, gd T cells emerge as a distinct lymphocyte pop-ulation with a unique and broad functional repertoire,and with important roles in Ab responses, inflammationand tissue repair. They also are revealed as a potentiallyuseful target for immune intervention. The Journal ofImmunology, 2010, 184: 4055–4061.

Unlike B cells and ab T cells, gd T cells were dis-covered through molecular means instead of by wayof their functions. Key questions remain concerning

possible functional differences between ab T cells and gdT cells, the significance of the organization of gd T cells intoa system of specialized subsets, and the function of the gdTCR. Explanations are needed for why gd T cells often re-spond faster than ab T cells and how sometimes in very smallnumbers they exert powerful effects on inflammatory re-sponses and tissue physiologies. Answers to these questionscould revise conventional immunological concepts, and theymight open new avenues for immunotherapy. In this briefreview, we examine in vivo gd T cell functions as revealed inmouse models.

Development of gd T cell function

From the studies in mouse models, it appears that thedevelopment of gd T cell function begins in the thymus andcontinues in the periphery, where environmental influencesmodulate developmental pathways. Fig. 1 shows a speculative

scenario of the development of gd T cell function in threemajor stages.

Early functional commitment in the thymus (stage 1)

The gd T lymphocytes arise from a common thymocyteprogenitor for ab and gd T cells during development in thethymus. Lineage commitment and potential appear to beinfluenced by several factors (1, 2), and commitment mayoccur at more than one developmental stage (3). Although theTCR type per se does not determine the lineage decision,TCR signal strength appears to determine lineage fate anddevelopmental stage of lineage choice (4, 5). TCR signals andtheir different strengths may continue to be important insubset-specific functional differentiation and commitment(Ref. 6 and below). Studies with gd TCR-expressing thy-mocytes indicated early on that certain subsets already acquirefunctional competence while in the thymus. Thus, thymo-cytes expressing TCR-gd and resembling NKT cells werefound to produce IL-4 (7), and a subset of adult gd TCR+

thymocytes that expressed Thy-1 at low levels could be in-duced to secrete IL-3, IL-4, IL-10, and IFN-g, in contrast toThy-1hi cells that only secreted IFN-g (8). The Thy-1lo thy-mocytes were barely detectable in newborn mice and in-creased during the first 2 wk after birth (8), but a later studysuggested that most originated from fetal precursors (9). Vg1+

gd T cells represent one of the major subsets in the secondarylymphoid organs and circulation of mice (10), and they areassociated with distinct functional roles (see below). Inkeeping with the idea of subset-specific differentiation, the IL-4–producing thymocytes all express TCRs encoded by Vg1(8, 9). While investigating gd TCR+ thymocytes for theirability to regulate allergic airway hyperresponsiveness (AHR),we found that in vivo-transferred Vg1+ thymocytes enhancedAHR, whereas Vg4+ thymocytes had no effect (11), pre-empting at least in part the functional pattern we had notedfor peripheral gd T cells (12). Interestingly, the gd lineage-derived AHR enhancers are not those that produce IL-4 andIL-13 (11), unlike the above-mentioned NKT-like gd T cellpopulation. This indicates that the Vg1+ thymocyte pop-ulation contains more than functionally committed cell type.

*Integrated Department of Immunology, National Jewish Health, Denver, CO 80206;†University of Colorado at Denver Health Sciences Center, Denver, CO 80220; ‡Collegeof Life Sciences, Nankai University, Tianjin, China; xDepartment of Pediatrics, College ofMedicine and Medical Research Institute, Chungbuk National University, Cheongju,Korea; and {Department of Ophthalmology, Doheny Eye Institute, University of SouthernCalifornia, Los Angeles, CA 90033

Received for publication January 5, 2010. Accepted for publication January 26, 2010.

This work was supported by National Institutes of Health Grants AI40611 andHL65410 (to W.K.B.), AI44920 and AI063400 (to R.L.O.), Grant 2007CB914801from the National Basic Research Program of China, and National Outstanding YoungScientist Award 30725015 from the National Science Foundation of China (to Z.Y.).

Address correspondence and reprint requests to Dr. Willi K. Born, Integrated Depart-ment of Immunology, National Jewish Health, 1400 Jackson Street, GB K409, Denver,CO 80206. E-mail address: bornw@njhealth.org

Abbreviations used in this paper: AHR, airway hyperresponsiveness; DC, dendritic cell;DETC, dendritic epidermal T cell.

Copyright� 2010 by TheAmerican Association of Immunologists, Inc. 0022-1767/10/$16.00

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Many gd TCR+ thymocytes are already capable of pro-ducing TNF-a and IFN-g upon activation in vitro (11),a bias that is maintained in the periphery (13). Thymocytesexpressing gd TCRs with a known specificity for the T10/T22 nonclassical class I molecules may express different Vgsand Vds and only share a common Dd motif (14, 15). Thesecells were shown to differentiate into IFN-g rather than IL-17producers dependent on TCR-ligand interactions in thethymus (16). However, development of IL-17–producing gdT cells in the thymus has its own particular requirements (17).Finally, functional differentiation of thymocytes expressingthe invariant Vg5Vd1 TCR of dendritic epidermal T cells(DETCs) in mice depends on thymic expression of Skint 1,an Ig-like molecule expressed on epithelial cells (18), whichmight be a ligand of this TCR.These data in mice show that many, if not all, thymic

precursors of peripheral gd T cells leave the thymus witha defined and limited functional potential.

Polyclonal functional induction in periphery (stage 2)

Many peripheral gd T cells in mice appear to be “resting yetactivated” (19) (i.e., they acquire an intermediate state ofactivation from whence polyclonal responses might be elicitedwith little further stimulation). Perhaps this intermediate statedepends on tonic signaling by cross-reactive gd TCRs, asenvisaged some time ago for certain ab T cells (20). Theunexplained “spontaneous” reactivity of hybridomas express-ing Vg1+ gd TCRs described many years ago might be an invitro correlate, at least for this subset (21). Peripheral gdT cells, which leave the thymus as functionally committedprecursors, are either already functionally competent or can beinduced to become competent in short order. With the ex-ception of two related populations in mice that express in-variant TCRs and directly colonize peripheral epithelia andmucosae (22), most peripheral gd T cells seem to recirculateand temporarily reside in the lymphoid tissues.A detailed comparison of murine and human gd T cell

populations is still lacking. We examined the mouse Vg1+ andVg4+ gd T cells, because these subsets resemble the much-

studied recirculating gd T cells present in human peripheralblood. Both reside in the murine spleen, and both depend fortheir functional development on CD8+ dendritic cells (DCs)(11, 23), a cell type present in thymus and secondary lymphoidorgans including the spleen, but not in peripheral nonlymphoidtissues (24). Our data suggest that although both of these gd Tcell types are already functionally committed, they differ intheir requirement for peripheral functional induction (12, 25).When transferred into secondary recipients, splenic Vg1+ gd

T cells can exert dramatic functional effects in various mousemodels of disease (see Table I). Inmodels of allergic AHRand inthe primary IgE response to OVA/alum (a model of adjuvant-supported vaccination), where they have a response-enhancingeffect, these cells do not need to be induced in any way (12, 42).In fact, even as HSAhi thymocytes, they already have the abilityto enhance AHR, following transfer into gd T cell-deficientrecipients (11). Whereas the IgE-enhancing gd T cells may becontainedwithin theNKT-like fraction ofVg1+gdTcells (39),the AHR-enhancing cells are not (see below) (42). Nevertheless,the AHR-enhancing cells also do not require induction.However, AHR-enhancing gd T cells are functionally in-competent in mice lacking certain cytokines and receptors. Inthese mice, they can be induced to become fully functional byperipheral stimulation with OVA/alum (11), revealing someflexibility in their developmental pathway. It thus appears thatseveral types of Vg1+ gd T cells, if not all, experience early in-trathymic programming/functional induction.Vg4+ gd T cells also affect disease outcome in various mouse

models, but unlike theVg1+ cells, they require peripheral signalsto become functional. In contrast toVg1+ cells, we observed thatVg4+ cells suppress AHRand the primary IgE response toOVA/alum but require immunization or repeated challenge with Agto develop (25, 39, 43). Thus, Vg4+ cells might bypass someof the intrathymic programming that defines the Vg1+ cells.However, their functional dependence on CD8+ DCs in donormice suggests that they receive developmental signals as well,whether in thymus or periphery (23).Moreover, although Vg4+

cells can be peripherally induced to suppress AHR and IgE,Vg1+ cells cannot. Such suppressor-inducing conditions do notseem to have any effect on the Vg1+ AHR enhancers but ren-dered Vg1+ IgE enhancers nonfunctional, although they didnot turn them into IgE suppressors (39). Thus, although there issome functional plasticity within either subset, the two do notfunctionally overlap. Both Vg1+ and inducible Vg4+ cell typesare highly effective regulators of AHR and IgE in vivo (38, 39,42) but appear to exert their functional effects as polyclonalunselected populations because they express diverse TCRs, andthe treatments used to induce function do not lead to substantialchanges in their TCR repertoires (25, 39).

Peripheral induction of Ag-presenting functions

Studies with ovine, human, and murine cells established thatperipheral gd T cells can be induced to acquire Ag-presentingfunctions (44–46), and a recent report characterized humangd T cells as professional phagocytes (47). Because all of thesestudies were done in vitro, it remains to be seen whether Ag-presenting gd T cells develop in vivo and are capable ofinfluencing Ag-specific immune responses.In contrast to human gd T cells, which express MHC class II,

in vitro expression of MHC class II molecules by murine cellsgd T cells has been detected but is limited to recently activated

Stage 1 Stage 2 Stage 3

P

AC

B

C

AC

APC

Memory?

S

S

S

S S

S

Thymus Secondary lymphoid tissues

I

Periphery

B BC I,A,B

FIGURE 1. Functional development of gd T cells in stages—a speculative

scenario. Stage 1 represents intrathymic differentiation under the influence of

the thymic environment into subset-segregated functionally committed gd

thymocytes (I, A, B, and C); at least some cells reach functional competence

already at this stage (AC); cells expressing invariant gd TCRs (I) may follow an

abbreviated path of differentiation. Stage 2 represents differentiation of some

subsets within secondary lymphoid tissues, induced by other cell types (e.g.,

activated DCs). At this stage, functionally competent cells (I, AC, and BC) are

capable of mounting polyclonal, subset-specific responses. Stage 3 represents

TCR-dependent peripheral selection of clones (S) within subsets. Activated

stages 2 and 3 gd T cells might transiently convert to APCs, and especially stage

3 gd T cells might be able acquire characteristics of memory cells.

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TableI.

ContributionofmurinegdTcells

topathogenesisandpathology

Model

gdTCells

(Net

Effect)

Vg1+

Vg4+

Vg5Vd1+(Invariant)

Vg6Vd1+(Invariant)

References

Skin

wound

Protective

Protective

(promotewoundhealing)

26,27

L.monocytogenesbacterialinfection

Protective

Pathogenic

(decreaseresistance)

Noeffect

28

WestNilevirusinfection

Protective

Protective

Pathogenic

(promoteencephalitis)

29

Respiratorysyncytialvirusinfection

Pathogenic

Pathogenic

(proinflam

matory)

30

Bacillussubtilisexposure;hypersensitivity

pneumon

itis

Protective

Protective,prevent

lungfibrosis

31

CoxsackievirusB3-inducedmyocarditis

Protective

Protective

(anti-inflam

matory)

Pathogenic

(proinflam

matory)

32

Experim

entalautoim

muneuveitis

Pathogenic

33

Collagen-inducedarthritis

Variable

Noeffect

Pathogenic

(proinflam

matory)

34

Heymann’snephritis;adriam

ycin-induced

nephritis

Protective

Protective

(anti-inflam

matory)

35,36

AllergicAHR

Variable

Pathogenic

(proinflam

matory)

Protective

(anti-inflam

matory)

12,37

PrimaryIgErespon

seto

OVA/alum

(vaccination)

Variable

Enhancing

Inhibitory

38,39

Subcutaneousmelanom

aProtective

Noeffect

Protective

40;Z.Yin,personalcommunication

Environmentalexposure

(ozone)-inducedAHR

Pathogenic

Pathogenic

(mediate

AHR)

Noeffect

41

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cells (46). When highly enriched gd T cells were restimulated invitro with plate-bound anti-CD3« and anti-CD28 mAbs, acti-vated gd T cells lost surface gd TCR expression while gainingMHC class II. Because of the absence of surface TCR, these cellsbecame essentially “invisible” but could be identified asgdTcellsby intracellular staining for TCR-d (46). It is thus conceivablethat MHC class II+ gd T cells in vivo have escaped investigatorscrutiny because of a loss of TCR expression. Taken togetherwithMHC class II, the in vitro-restimulated gdT cells expressedCD40 and CD80, and they were capable of presenting peptideAgs to MHC class II-restricted ab T cells with specificities forthe uveitogenic peptide IRBP1–20 (48) and the encephalitogenicpeptide MOG35–55 (49). These data suggest that stimulationof peripheral gd T cells via the TCR can induce an alternativefunctional program that converts them (transiently) to APCs.However, activation with cytokines might induce the conversionalso (46), and the relative importance of these mechanisms re-mains to be determined.

Clonal selection in the periphery (stage 3)

Studies in humans (50, 51) and mice (34, 52, 53) suggest thatfunctionally committed gd T cells can be peripherally selectedvia TCR-ligand interactions. The putative TCR ligands are stillunknown. This peripheral selection appears to be a slow pro-cess, perhaps largely limited to chronic disease conditions, andless effective than clonal selection of Ag-specific ab T cells.A recent study in the collagen-induced arthritis model in

DBA/1 mice illustrates this process (34). In these mice, gdT cells responded to injections of collagen inCFA, Vg4+ cells inparticular became activated, expanded, infiltrated the joints,and were shown to exacerbate the disease. Intracellular stainingshowed that the infiltrating Vg4+ gd T cells expressed IL-17,a cytokine associated with T cell pathogenicity in severalmodelsof autoimmune disease. In the course of this response, the TCRrepertoire within the Vg4+ subset became much more focused,suggesting that the oligoclonal response was driven by a specificligand (34). The putative ligand driving this peripheral responsedoes not appear to be collagen, but it might be contained withinCFA or be induced through inflammation (34).Two TCR-defined gd T cell subsets in mice, the DETCs in

the skin expressing invariant Vg5Vd1 TCRs and the gd T cellsexpressing the related invariant Vg6Vd1 TCRs, which colonizethe mucosae of the female reproductive tract and the lung, re-semble clonally expanded gd T cell populations (“I” in Fig. 1),although their invariant TCR appears to be selected in thethymus. These cells are activated by inducible autologous li-gands (54, 55), and they exert relatively uniform functions. Theactivated DETCs promote epithelial repair and wound healing(26, 56). Vg6Vd1+ gd T cells seem to respond to inflammation(55, 57), might play an immune-regulatory role during preg-nancy (58), exert antibacterial activities in the lung, and inhibitthe development of pulmonary fibrosis (31). The evolutionaryconservation of these pseudoclonal gd T cell populations inrodents—there is no human equivalent—might reflect a partic-ular need for their rapid responses early in development.

Evidence that the TCR remains involved in all stages of functionaldevelopment

At the onset of development, TCR-signaling supports thelineage decision between ab and gd T cells, with strong signalsthrough the gd TCR favoring gd T cell development (3–5).Subsequently, innate TCR interactions with autologous ligands

seem to play a role in the functional commitment of gd T cells(6, 16). It is not yet clear whether such TCR signals determinesubset differences in functional commitment (19). However,although still in the thymus, cells expressing different gd TCRsalready exhibit different functional potentials in vitro and invivo (11). Autologous ligands and their in situ expressionpatterns in the thymus might be detectable using soluble ver-sions of the gd TCRs in question, as has been demonstrated inprinciple in vitro (59, 60).Polyclonal activation and functional induction of committed

cells in the peripheral lymphoid organs do not necessarily in-volve the TCR andmight be accomplished with cytokines alone.However, gd T cells at this stage can be activated via the TCR,with subsequent changes in function. Most obviously perhaps,the polyclonal conversion to Ag-presenting functions in vitrocan be induced by TCR engagement (46). A role for poly- oroligoclonal TCR engagement is also suggested by data linkingthe expression of certain VgVd pairs with distinct functions.Thus, only Vg1Vd5+ cells promote AHR in mice hyper-sensitized to OVA, and Vg1Vd6+ gd T cells express a uniquecytokine profile when compared with other Vg1+ cells (8, 9).The ability of polyclonal Vg1+ hybridomas to secrete cytokines“spontaneously” suggests that their TCRs might detect self-determinants (21, 61–64).Finally, clonal expansion in the periphery implicitly involves

TCR-ligand interactions, but putative ligands remain to beidentified.

Terms of functional engagement

Early and very rapid responses of gd T cells were found both inmodels of infection and exposure to injury. Thus, the influenceof gd T cells can be detected within a few hours of exposure toozone, in this case mediating nonspecific AHR (41). In thisshort time frame, expansion of gd T cells is not expected toplay a role in their function. In contrast, gd T cells can undergolarge expansions, and the largest expansions were found rela-tively late in infectious and chronic inflammation, with several100-fold increases of local gd T cell populations (31, 34).During inflammation, gd T cells often assume a regulatoryrole, as was first suggested in a model of pulmonary infectionwith influenza virus (65), and later demonstrated in mice in-fected with Listeria monocytogenes (66). In Listeria infection ofthe liver, gd T cells were found to be required for the resolu-tion of neutrophilic inflammation and the subsequent in-filtration of macrophages (67). However, the same gd T celltypes that respond in infectious inflammation can also respondin sterile inflammation (55). Elegant studies with gd T cells inthe skin expressing an invariant TCR revealed that these cellsrespond locally, and very rapidly, to tissue injury (27). Histo-logical analyses of recent skin wounds showed activated gdT cells proximal to the wound edge, and further studies de-termined that the gd T cells must be able to recognize kera-tinocytes (68) and induce them to produce hyaluronan, whichin turn attracts macrophages that are instrumental in the repairprocess (26, 69).However, the influence of gd T cells is also evident in the

absence of injury and inflammation, most notably perhaps inB cell development. That gd T cells can provide B cell helpand support Ab production in immunized or infected micehas been known for some time (70, 71). There is also evidencethat they might regulate peripheral levels of specific Abs (38,

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72). More recently, it has come to light that they even supportand regulate Abs that develop without intentional immuni-zation (39, 73, 74).

Functional balance

Comparisons of the roles of Vg1+ andVg4+ gdT cells now havebeenmade in a number ofmousemodels of disease (Table I), andthe functional contributions of these subsets often appear to beopposed. Thus, when cells contained within one subset exacer-bate disease pathology, cells within the other diminish it (12, 28,29, 32, 33, 37, 40) (Z. Yin, unpublished results). Functionalequilibrium may be reached at different levels, depending onexternal influences. For example, we found that airway allergenchallenge strengthens the IgE-suppressive capability of Vg4+

cells while at the same time diminishing the IgE-enhancing ca-pability of Vg1+ cells (39). It is still unclear whether the exampleof Vg1+ and Vg4+ gd T cells can be generalized. Perhapsfunctional equilibrium is also achievable between cell types of lessclosely related lineages (e.g., gd T cells and ab T cells). In anycase, one lesson from these studies is that depleting or recon-stituting total gd T cells might reveal little in terms of functionaleffects when functions are balanced, and the full regulatory rangeof these populations can easily be missed (38, 39, 42, 75).

When and where gd T cell functions are needed

Because gd T cells are the first T lymphocytes to arise inontogeny (76, 77), it seems likely that they play an importantrole in immune protection early in development. Studies inmouse models and with human cells support this notion.Specifically, in young mice infected with Eimeria vermiformis,an intestinal parasite responsible for coccidiosis, gd T cellswere shown to be required for host resistance against thispathogen (78). In contrast, in adult mice, ab T cells are bothnecessary and sufficient for protection. The relative in-effectiveness of ab T cells in young mice might be due to anearly Th2 bias of these cells so that gd T cells come tofunction as a Th1 substitute (79). Human neonates harborhighly active gd T cells. By comparison with ab T cells, thesecells exhibit stronger, pleiotropic functional responsiveness,and they lack deficits in IFN-g production present in neonatalab T cells (80). The gd T cells in infants respond strongly toimmunization with bacillus Calmette-Guerin vaccine (81),and environmental factors are likely to shape the neonatalrepertoire of gd T cells (82), with possible long-term con-sequences for immune functions. Even prior to birth, gdT cells might protect the developing organism. The re-productive tract in female mice harbors a distinct populationof gd T cells (83). During pregnancy in mice, gd T cellsincrease vastly in numbers as the placenta develops (58). Atleast some of these cells appear to be capable of recognizingdeterminants on trophoblasts (84). Whether such cells play animmune-regulatory role or perhaps protect the fetus againstinfections remains to be determined (85, 86).Because gd T cell subsets are locally segregated, it seems

likely that they also have specific functions related to the tissuesin which they reside. Perhaps the most impressive example ofthis is the DETCs in rodents, which selectively colonize theepidermis and play a distinctive role in wound healing (26, 27,56). Apparently, this function is so important that it justifiesthe existence of an entire gd T cell subset expressing an in-variant gd TCR (Vg5/Vd1) (87). Whether these cells are also

functionally homogeneous remains to be tested rigorously (88).A second type of gd T cell in mice and rats expressing an in-variant TCR (Vg6/Vd1) also has local functions in the tissues.In contrast to the DETCs, however, these cells form smallersteady-state populations, which expand to a much larger sizeonly when their functions are required (57). Cells expressingVg6/Vd1 invariant gd TCRs in the lung (89) expand duringchronic exposure with live bacteria (31). Importantly, cellswithin this subset help preventing pulmonary fibrosis (90).Vg6/Vd1 TCR+ cells also expand in nephritis of mice and rats(35, 36, 91) and in testicular inflammation in mice (55), ineither tissue with a protective effect. The heterogeneous gdT cells in the lymphoid tissues likely have multiple functions.For example, Vg1+ cells seem to play a role in driving andregulating background levels of B cell differentiation (39, 73,74), without apparent need for stimulation. When the immunesystem is challenged through vaccination or during infections(70, 71), they continue to support B cell differentiation, butnow the help from ab T cells becomes dominant (39). The gdT cells, which can be found in the lymphoid organs, reappearin the peripheral nonlymphoid tissues where they can be in-duced to engage functionally (Table I). Vg4+ cells, for example,contain inducible regulators of lung function, capable of in-hibiting bronchoconstriction (43). They also contain inducibleproinflammatory effectors, as demonstrated in mouse modelsof coxsackievirus B3 infection (32, 92), of respiratory syncytialvirus infection of the lung (30), and of collagen-induced ar-thritis (34). Vg1+ cells in the lymphoid tissues tend to opposethe effects of Vg4+ cells in the tissues (12, 32, 39), though notalways. Besides Vg4+ and Vg1+ gd T cells, there are other gdT cells in the lymphoid tissues (e.g., up to 50% of splenic gdT cells), whose functions have not yet been studied separately.Investigations of such cells in mice likely will broaden theperspective of distinct gd T cell functions. In contrast, the mainexperimental source of human gd T cells continues to be pe-ripheral blood, which contains a more limited spectrum of gdT cells (93).

Is participation in the stress response a distinguishing function of gdT cells?

The idea that gd T cells play a key role in immune surveil-lance of stress in the tissues can be traced back to early days inthis field of research (94), and it continues to stimulatespeculation. A comprehensive analysis of this idea has beenrecently published by A. Hayday (19), who concluded that gdT cells indeed play a significant role in the immune responsesto stress. However, gd T cells are by no means the onlylymphocytes capable of recognizing and responding to cellularstress. Furthermore, there are constitutive gd T cell functionsthat are difficult to reconcile with a focus on cellular stress,because they occur under steady-state conditions. An exampleis the already mentioned role of gd T cells in B cell differ-entiation and the development of Abs. Although earlierstudies showed an involvement of gd T cells in induced Abresponses (38, 70, 71, 95, 96), recent observations suggesta far more critical influence of gd T cells on the developmentof polyclonal noninduced Abs (39, 73, 74), with potentialdownstream effects on immune competence (97). Moreover,assuming that the immune responses to stress are immediateand polyclonal, the slow peripheral selection of oligo- ormonoclonal gd T cells (34, 98) does not fit well either.

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However, the response to stress likely is one of several naturalcapabilities of gd T cells.

Why gd T cell functions are a potential target for immune intervention

The association of distinct functions with TCR-defined subsetsof gd T cells invites the targeting of these subsets with Abs forimmune intervention. Ab targeting of the TCR is nothing new,but gd T cells represent a special case. In this study, because thetargeting can be limited to small subsets with distinct functions,undesirable side effects of the Ab treatment (“cytokine storm,”immune deficiency) are expected to be minimal, because rela-tively few cells are involved. Maximal regulatory effects mightbe achievable by inactivating one subset while stimulating an-other, when gd T cell subset functions are balanced. Further-more, because distinct functions are associated with subsetsinstead of clones, the hurdle of developing clonotypic Abs doesnot exist, and a single Ab with a given subset specificity is likelyto be useful in different diseases and many patients.

ConclusionsAnimal models and especially mouse models of disease provideaccess to gd T cells and their functions in a manner that is notachievable with human beings. Studies in mice already havegenerated a far more comprehensive picture of gd T cell func-tions than could be obtained with human cell culture, and theyare likely to provide first-hand information in the future. Becausedifferences between gd T cells in primates and rodents exist, anyfinding inmice must be validated in humans, butmice and otheranimal models remain irreplaceable as discovery tools.

DisclosuresThe authors have no financial conflicts of interest.

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