Predisposed αβ T cell antigen receptor recognition of MHC and MHC-I like molecules?

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Predisposed ab T cell antigen re
ceptor recognition ofMHC and MHC-I like molecules?Sidonia BG Eckle1, Stephen J Turner1, Jamie Rossjohn2,3,4 andJames McCluskey1,4
The diverse ab T cell receptor (TCR) repertoire exhibits versatility

in its ability to generate antigen (Ag) receptors capable of

interacting with polymorphic Major Histocompatibility Complex

(MHC) molecules and monomorphic MHC-I like molecules,

including the CD1 and MR1 families. Collectively, these

evolutionarily related Ag-presenting molecules present

peptides, lipids and vitamin B metabolites for T cell surveillance.

Interestingly, whilst common TCR gene usage can underpin

recognition of these distinct classes of Ags, it is unclear whether

the ‘rules’ that govern abTCR-Ag MHC interactions are shared.

We highlight recent observations in the context of TCR biases

towards MHC and MHC-I like molecules.

Addresses1 Department of Microbiology & Immunology, Peter Doherty Institute for

Infection and Immunity, University of Melbourne, Parkville, Victoria 3010,

Australia2 Department of Biochemistry and Molecular Biology, School of

Biomedical Sciences, Monash University, Clayton, Victoria 3800,

Australia3 Institute of Infection and Immunity, Cardiff University, School of

Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom

Corresponding authors: Rossjohn, Jamie ([email protected])

and McCluskey,

James ([email protected])

4 Joint senior authors.

Current Opinion in Immunology 2013, 25:653–659

This review comes from a themed issue on Immunogenetics and

transplantation

Edited by Miles Davenport and Deborah K Dunn-Walters

For a complete overview see the Issue and the Editorial

Available online 29th August 2013

0952-7915/$ – see front matter, # 2013 Elsevier Ltd. All rights

reserved.

http://dx.doi.org/10.1016/j.coi.2013.07.010

IntroductionThe ab T cell antigen receptor (TCR) can recognize

antigens presented by products of the MHC gene family.

MHC class I (MHC-I) and MHC class II (MHC-II) mol-

ecules are highly polymorphic receptors that bind peptide-

based (p) antigens. MHC-I-like molecules, which are

essentially monomorphic, present non-peptide antigens

to specialized T cell subsets, including Natural Killer T

(NKT) cells, Germline-encoded mycolyl lipid reactive

(GEM) T cells and Mucosal-associated invariant T

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(MAIT) cells [1–3]. MHC-I like molecules share the same

overall structure as MHC-I, yet exhibit customized chemi-

cal properties suited to bind distinct specific classes of

ligand [4]. For example, the CD1 family and the MHC-I

related molecule MR1, are ideally suited to bind lipid-

based and vitamin B based metabolites respectively [4,5��].Moreover the MHC-I molecule can, in part, accommodate

non-peptide-based ligands, as exemplified by HLA-linked

drug hypersensitivities [6��,7]. The host uses a diverse

repertoire of ab TCRs to engage these various Ag-pres-

entation platforms. Intriguingly however, TCR biases are

observed in the MHC-specific repertoire relevant to pro-

tective immunity and auto-immune-like disorders [8–10].

Moreover, biased TCR usage can underpin CD1d and

MR1-restricted recognition [1]. However, there are also

examples of overlapping TCR gene usage against peptide,

lipid and vitamin B Ags. What factors drive these TCR

biases and what does this mean about the hard wiring of

TCRs towards these distinct Ag-presenting molecules?

Here we review recent advances in the field of TCR

recognition of MHC and MHC-I-like molecules.

T cell repertoire selection and pre-determinedbiasTCR genes rearrange their exons during the develop-

ment of T cells in the thymus, and when combined with

mechanisms such as addition/deletion of nucleotides at

exon junctions, generate a diverse repertoire of Ag-recep-

tors. Although thymic selection was first appreciated in

the context of MHC-restricted immunity [11�], it is now

clear that the ab T cell repertoire is also selected against

MHC-I-like molecules [12,13]. While it has long been a

goal of the field to determine what the rules are that

govern ab TCR recognition of classical pMHC com-

plexes, these have remained elusive. Ironically, more

recent studies of ab TCR recognition of CD1d-Ag and

MR1-Ag complexes have provided key insights into

conserved features of ab TCR recognition. Accordingly,

we shall initially review MHC-restriction and sub-

sequently discuss the emerging findings in CD1d-

restricted and MR1-restricted immunity.

Thymic selection favours T cells that exhibit weak reac-

tivity for self-pMHC and deletes T cells with strong self-

pMHC reactivity, thereby resulting in MHC ‘restriction’

of T cells that are predisposed to recognizing host MHC

[14]. The concept of, and evidence for, germline hard

wiring of the TCR to recognize MHC has intrigued the


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654 Immunogenetics and transplantation

field for decades [15]. Both the MHC and TCRs are

thought to have evolved about 500 million years ago in

cartilaginous fish [16], thus potentially allowing for coe-

volution of TCR germline encoded elements to interact

with MHC molecules. An alternative view postulates that

MHC-restricted T cells are selected during positive

selection from a preselected repertoire with unbiased

specificities [17,18�,19]. Here, TCR specificities are

thought of as behaving in an antibody-like fashion where

thymic selection tunes unbiased reactivity towards an

MHC-affinity window that skews their mature reactivity

towards self-MHC-recognition (Figure 1).

Figure 1

Preselectionrepertoire

Thymicselection

Peripheralrepertoire

Bia

sed

Unb

iase

d

non-MHC reactive T cell

T cell reactive with MHC, with high, intermediate,low affinity/avidity

T cells dying by neglect

Negatively selected T cells

Positively selected T cells

Current Opinion in Immunology

Models of selection from an unbiased versus biased (hard wired) TCR

repertoire. The biased and unbiased preselection repertoires consist of T

cells (grey disks) reactive with MHC. The unbiased preselection

repertoire contains in addition T cells that are non-MHC reactive. T cells

reactive with MHC can have high, intermediate or low affinity/avidity for

MHC. During thymic selection T cells interact with MHC presented in the

thymus on APCs (orange irregular shape) if they are MHC-reactive. Only

T cells that interact with intermediate affinity/avidity with MHC get

selected and appear in the peripheral repertoire. In contrast T cells with

low affinity/avidity or high affinity/avidity die by neglect and get

negatively selected, respectively. In addition, non-MHC reactive T cells

present in the unbiased T cell repertoire will not encounter MHC in the

thymus and die by neglect.


Hard wiring of TCR reactivity for self-MHC suggests the

existence of some ‘hidden logic’ underpinning pMHC

recognition. Conversely, thymic filtration of unbiased

TCRs to retain only those with a narrow window of

affinity for pMHC does not a priori presuppose stereo-

typic patterns of MHC recognition. To put it another way,

how T cells are guided to interact with MHC molecules

remains unclear. Nevertheless, studies investigating viral

immunity; T cell alloreactivity [20]; co-receptor usage

[18�], TCR bias [9], and the TCR-MHC-I-like axis [1],

have provided some insight, albeit often conflicting, into

this issue of the driving force between the TCR-pMHC

interaction. Front and centre stage to many of these

studies are structurally focused investigations

[1,11�21�,22,23�,24,25].

Structural correlates of MHC restrictionDespite the growing list of distinct TCR-pMHC struc-

tures, the ability to define rules that govern classical

pMHC interactions has proven difficult [21�]. Further,

these investigations involve a limited array of MHC

allotypes, which is an issue as the Human Leucocyte

Antigen (HLA) locus is the most polymorphic region in

the human genome. With that in mind, some general

observations can be made. For example, the TCR sits

atop the pMHC, forming an imperfect interface that is

consistent with the weak affinity of this interaction, with

the Va and Vb domains of the TCR docked over the

MHC-I a2-helix and a1-helix respectively [21�]. As this

approximate docking mode is maintained between differ-

ent TCR-pMHC complexes, it suggests some ‘logic’ to

this key interaction. However, this logic appears not to

rest with conserved structural ‘landing spots’ on the

MHC, such as the previously hypothesized ‘restriction

triad’ [26,27]. Moreover, the precise TCR binding modes

can vary markedly for individual TCR-pMHC complexes

and likely reflect the polymorphic pMHC landscape, and

diversity within the vast TCR repertoire.

Some studies consider the TCR’s germline-encoded

regions (the Complementarity Determining Regions

(CDRs) 1 and 2) as the key components that determine

MHC interactions, while the hypervariable CDR3 loops

‘read-out’ the antigenic cargo [23�,28]. Indeed, conserved

interactions (‘codons’) between two tyrosine residues

(Y46 and Y48) within the CDR2b loop of some Vb8.2+

TCRs and some MHC molecules appear maintained,

throughout evolution (Figure 2a,b) [11�,29]. Indeed,

Y48 was determined to be important in T cell positive

selection of CD4+ and CD8+ T cells, while Y46 was only

important for the selection of CD4+ T cells, suggesting

these residues are key for determining MHC-I vs MHC-

II restriction [30]. Nevertheless, even within the Vb8.2

family, varied docking modes on distinct self-MHC and

allo-MHC molecules are observed [31��,32], leading to a

concept of ‘wobble’, whereby that the same V-region

may bind to alternative pMHC-I molecules in a slightly


Rules of ab TCR recognition Eckle et al. 655

Figure 2

Y46

Y48 Y46

Y48

Y46 Y48

Y46

Y48

MHC-I

MHC-II

CD1d


Contrasting modes of CDR2b (Vb8.2) recognition on MHC-I, MHC-II and

CD1d. Top-views of MHC helices with isolated CDR2b loops on MHC-I

(H-2Kb, YAe62 TCR: pink, PDB ID: 3RGV; H-2Kb, 2C TCR: violet, PDB

ID: 2CKB), MHC-II (I-Ab, YAe62 TCR: blue, PDB ID: 3C6O; I-AU, 1934

TCR: cyan, PDB ID: 2PXY; I-Ak, D10 TCR: smudge, PDB ID: 1D9K) and

CD1d (NKT TCR: yellow, PDB ID: 3HES). CDR2b Y46 and Y48 are

displayed in stick format.

different mode (Figure 2a) [28]. Moreover, altered Vb8.2

binding modes induced by differential Va-chain pairing

can also affect the role of these residues encoded within

the CDR2b loop [33�,34]. Whilst the degree of differ-

ence/similarity could be considered semantic, it is import-

ant to note that in MHC-restricted immunity, small (less

than 1 A) shifts in MHC helices can dictate T cell

repertoire selection and protective immunity [35], and

have also been linked to taboo mismatches in transplan-

tation [36]. Thus, the thought-provoking ‘codons’ con-

cept needs to be considered a partial and incomplete

structural explanation of TCR-pMHC hard wiring.

In line with this view, a recent analyses of the unique

TCR-pMHC-I structural database [21�] show that the


self-perpetuating CDR1/2-MHC and CDR3-peptide

dogma is incorrect, as the germline encoded residues

frequently contact the peptide, whilst the CDR3 regions

often make crucial contact to the MHC [37,38]. Instead,

synthesis of all the available data indicates that TCRs

have a peptide-centric view that drives the MHC-

restricted interaction. Indeed, the protective immune

response is triggered by a foreign peptide within the

MHC; T cell mediated alloreactivity can be attributed

to peptide-dependent molecular mimicry [39��]; the

impact of germline-encoded TCR polymorphisms are

attributable to peptide-centric charge complementarity

[40]; diverse TCR docking modes atop a common pMHC

can reflect peptide-driven contributions [38,41]; TCR

recognition of ‘super-bulged peptides’ can be markedly

peptide centric, or involve atypical MHC-contact sites

[26,42,43]. Thus, we propose that the peptide acts as the

initial ‘lynch-pin’ for the TCR-pMHC interaction while

the MHC interactions subsequently act like a ‘Velcro’ to

stabilize TCR binding. Clearly, many more unique TCR-

pMHC structures are required to shed further insight into

MHC-mediated immunity.

TCR interactions with MHC-I like moleculesThe innate-like NKT and MAIT cells draw their TCR

from the same ab-TCR repertoire as MHC-restricted T

cells and yet they interact with CD1d and MR1 respect-

ively. Given the evolutionary conserved nature of both

MR1 and CD1d, we could expect studies of TCR-CD1d/

MR1 interactions to provide insights into the hard wiring

or TCR recognition of MHC and MHC-I like molecules.

TCRs expressed by Type I NKT cells generally exhibit

invariant a-chain usage (Va24-Ja18 in humans, Va14-

Ja18 in mice), and a restricted Vb repertoire (Vb11 in

humans and Vb8.2, 7 and 2 in mice) [44]. Interestingly,

despite common Vb8.2 (and orthologous Vb11) usage in

MHC-restricted and CD1d-restricted immunity, the

location of the corresponding CDR2b regions atop these

MHC and MHC-like molecules is markedly different

(Figures 2c and 3) [45]. This suggests that there is

inherent flexibility within the TCR gene segments to

accommodate alternate binding modes on distinct MHC-

Ag landscapes. What is more astounding is that despite

the varied Type I NKT TCR gene usage [46–49], and a

variety of chemically distinct lipid-based antigens recog-

nized by Type I NKT cells [50], the mode of Type I

NKT TCR-CD1d-Ag docking is conserved – namely it

adopts a parallel docking mode above the F0-pocket of

CD1d (Figure 3) [51,52]. Thus, distinct components of

the available abTCR repertoire are utilized to recognize

CD1d-Ag in the same way. Indeed, Type I NKT TCRs

act more like a pattern recognition receptor in which the

germline-encoded regions of the TCR solely interact with

the lipid antigen [1,53].

The inherent flexibility within the available abTCR

repertoire to see restricted CD1d-Ag complexes is



Figure 3

TCR-MHC-peptide

Type I NKT TCR-CD1d-αGalCer

MAIT TCR-MR1-RL-6-Me-7-OH

CDR1α

CDR2α

CDR3α

CDR2β

CDR1β

CDR3βCDR1α

CDR2α

CDR3αCDR2β

CDR1β

CDR3β

CDR1α

CDR2α

CDR3α

CDR2β

CDR1β

CDR3β

β2mβ2mβ2m

CD1d MR1 MHC-I

Vα VβVα Vβ Vα Vβ

Cα Cβ Cα Cβ Cα Cβ

MAIT-TCR NKT TCR TCR

peptide RL-6Me-7-OH

αGalCer

(a)

(b)


TCR recognition of peptides, lipids and vitamin B Ags. LC13 TCR in complex with HLA-B8-FLR (left panels, PDB ID: 1MI5), MAIT TCR in complex with

MR1-RL-6-Me-7-OH (middle panels, PDB ID: VL4V) and NKT TCR in complex with CD1d-aGalCer (left panels, PDB ID: 3HE6). Depicted are the side-

views of the overall complexes (a) and the top-views of the Ag-MHC with isolated CDR loops and centres of mass for the Va and Vb domains (black

spheres) (b). TCR a — chains are coloured in pale green, CDRa — loops in blue; TCR b — chains are coloured in cyan, CDRb — loops in green. MHC

molecules are coloured in grey; peptide, vitamin B and lipid antigens are shown in stick format and coloured in pink, light green and yellow,

respectively.

evidenced by analysis of Type II NKT cells. Here

Type II NKT cells, which exhibit more diverse TCR

usage than Type I NKT cells, can dock in a markedly

different manner onto CD1d [54�,55�]. As observed with

some conventional abTCR-pMHC interactions, the non-

germline encoded regions of sulfatide-reactive TCRs

dominated contacts with the Ag and the Ag-presenting

molecule.

MAIT cells also exhibit invariant TCR a-chain usage

(Va7.2-Ja33 in humans) and express a limited repertoire

of TCR b-chains (Vb2,13 in humans) [56] and recognize

MR1 presenting vitamin B metabolites [5��]. Interest-

ingly, the recently described GEM T cells, which are

restricted to CD1b presenting GMM, also exhibited

biased TRAV1-2 usage, although it remains to be deter-

mined how these GEM TCRs interact with CD1b-Ag [2].


The structure of the human MAIT TCR complexed to

MR1 bound to a non-activating and activating ligand

provided the first definitive insight into vitamin B metab-

olite mediated recognition (Figure 3) [57�]. The MAIT

TCR docked approximately centrally and orthogonally to

the main axis of the MR1-Ag-binding cleft, consistent

with a xenoreactive MAIT TCR-MR1 complex in which

ligands were hypothetically modelled into the MR1 cleft

[58]. Alongside mutagenesis studies of the human MAIT

TCR-MR1 system [59], these findings revealed that the

Va7.2-Ja33 chain formed many contacts with MR1, while

the germline-encoded regions of the Vb chain played a

lesser role, although the CDR3b loop sat above the Ag,

and interacted extensively with MR1 [57�]. Several of the

residues from the invariant a-chain that contact MR1 are

either conserved or synonymously substituted across all

known eutherian and marsupial a-chain orthologues,



suggesting longstanding co-evolution of this TCR-MR1

interaction, consistent with the high sequence conserva-

tion of MR1 across species. Interestingly, the docking

mode of the MAIT TCR-MR1-Ag complex resembled a

Va7.2+ TCR-pMHC-I complex [60], indicating that

MAIT TCR recognition shared more ‘adaptive features’

than the innate-like characteristics of the Type I NKT

TCR. Nevertheless, it is likely that a common mode of

MAIT TCR-MR1 docking will underpin recognition of

any other (yet to be identified) MR1-restricted Ags.

ConclusionsPresently, the field of MHC-mediated immunity is con-

founded by the various docking strategies employed by

the T cell repertoire. Ironically, whilst the field of CD1

and MR1-restricted biology is less well established than

MHC-recognition, the ‘rules of engagement’ are much

clearer in these systems in which invariant TCR usage

seems to be a predominant driving force in recognizing a

monomorphic Ag presenting molecule. It is likely not to

be coincidental that the TRAV1-2 gene of the TCR has

been used for recognizing peptides, vitamin B metab-

olites and lipids bound to their respective Ag-presenting

molecules [2,57�,60]. Here, the TCR hard wiring seems

geared to interacting with the monomorphic MHC-I like

molecule as well as antigen, independent of the chemistry

of its antigenic cargo. Perhaps the field of MHC biology

could learn much from examining TCR recognition of

MHC-I like molecules.

AcknowledgementsThis research was supported by the National Health and Medical ResearchCouncil of Australia (NHMRC). S.J.T. was supported by an AustralianResearch Council Future Fellowship, J.R. was supported by an NHMRCAustralia Fellowship.

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54.�

Patel O, Pellicci DG, Gras S, Sandoval-Romero ML, Uldrich AP,Mallevaey T, Clarke AJ, Le Nours J, Theodossis A, Cardell SL et al.:Recognition of CD1d-sulfatide mediated by a type II naturalkiller T cell antigen receptor. Nat Immunol 2012, 13:857-863.

See annotation to Ref. [55�].

55.�

Girardi E, Maricic I, Wang J, Mac T-T, Iyer P, Kumar V, Zajonc DM:Type II natural killer T cells use features of both innate-like andconventional T cells to recognize sulfatide self antigens. NatImmunol 2012, 13:851-856.

This paper provides first insight into Type II NKT TCR recognition.

56. Gold MC, Lewinsohn DM: Co-dependents: MR1-restrictedMAIT cells and their antimicrobial function. Nat Rev Microbiol2013, 11:14-19.

57.�

Patel O, Kjer-Nielsen L, Le Nours J, Eckle SBG, Birkinshaw R,Beddoe T, Corbett AJ, Liu L, Miles JJ, Meehan B et al.:Recognition of vitamin B metabolites by mucosal-associatedinvariant T cells. Nat Commun 2013:4.

This paper provides first formal insight into how the MAIT TCR binds tovitamin B metabolites bound to MR1.





































































































































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mucosal associated invariant T cell receptor. J Exp Med 2012,209:761-774.

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Predisposed αβ T cell antigen receptor recognition of MHC and MHC-I like molecules?

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