T-cell receptor bias and immunity

Available online at www.sciencedirect.com

T-cell receptor bias and immunityStephanie Gras1, Lars Kjer-Nielsen2, Scott R Burrows3,James McCluskey2,* and Jamie Rossjohn1,*

Despite the potentially vast T-cell repertoire, biased ab T-cell

receptor (TCR) usage has emerged as a common theme in

immunity. Examples of TCR bias are observed in classical

polymorphic major histocompatibility complex (MHC)-

restricted immune responses as well as in T-cell responses to

non-classical, monomorphic Ag-presenting molecules, such as

CD1d. Recent data have implicated the structural landscape of

these antigen-presenting molecules as one of the drivers of

TCR bias. Here we review recent advances in the field,

focussing on structural data pertaining to biased TCR usage,

and discuss the implications for T-cell repertoire selection,

MHC restriction and therapeutic development.

Addresses1 The Protein Crystallography Unit, Department of Biochemistry and

Molecular Biology, School of Biomedical Sciences, Monash University,

Clayton, Victoria 3800, Australia2 Department of Microbiology & Immunology, University of Melbourne,

Parkville, Victoria 3010, Australia3 Cellular Immunology Laboratory, Queensland Institute of Medical

Research, Brisbane 4029, Australia

Corresponding author: McCluskey,

James ([email protected]) and Rossjohn, Jamie

([email protected])

Current Opinion in Immunology 2008, 20:119–125

This review comes from a themed issue on

Antigen Processing and Recognition

Edited by Emil Unanue and James McCluskey

Available online 18th January 2008

0952-7915/$ – see front matter

# 2007 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.coi.2007.12.001

IntroductionThe ab T-cell receptor (TCR) plays a central role in the

adaptive immune response, interacting with foreign pep-

tide antigens (Ag) in complex with the major histocom-

patibility complex (pMHC). The MHC is highly

polymorphic and distinct features within the peptide-

binding groove enables the MHC to present a wide array

of peptides, but nevertheless TCRs are highly restricted

to recognise host MHC molecules. In addition, the TCR

can also recognise lipid-based antigens that are presented

by the monomorphic CD1 family, which includes CD1d,

the only CD1 family member that is present in humans

and mice.

* Joint senior.

www.sciencedirect.com

To cope with this Ag diversity, the host possesses a

potentially vast T-cell repertoire and after positive [1–

3] and negative selection [4–6] the number of different

TCRs is approximately 107 in human and 106 in mice.

This TCR diversity is generated via gene rearrangement

within the variable domains of the TCR; namely the

variable (V) and junction (J) gene segments define the

Va chain whereas the Vb chain is composed of rearranged

V, D (diversity) and J genes segments (Figure 1). The

human locus for the TCR a chain is located on chromo-

some 14 and contains 43 Va genes (referred to here as

TRAV according to the immunogenetics database,

IMGT [7]) as well as 58Ja (TRAJ) gene segments.

The b TCR genes are located on the chromosome 7

and contain 42Vb, 2Db and 12Jb (TRBV, TRBD and

TRBJ, respectively) gene segments. In addition, there is

also junctional diversity V-(N)-J, V-(N)-D and D-(N)-J

produced by random insertions/deletions at these regions

(N represents ‘nucleotide’) [8,9] (Figure 1). This diversity

is manifested in the third complementarity determining

regions (CDR), which is the region of the TCR that

interacts with the bound peptide and glycolipid of

MHC and CD1d molecules respectively (Figure 1a and

c). The CDR3 loops that span the junctional region are

highly diverse in sequence and length. Despite this TCR

diversity and its importance in protective immunity, there

are a growing number of examples of TCR bias in anti-

viral immunity in which restricted Va and/or Vb usage as

well as restricted CDR3 conserved motif characterises the

immune response to defined antigens. A number of

different mechanisms may operate to shape the T-cell

repertoire, including thymic selection of the naı̈ve T-cell

repertoire, TCR avidity for the pMHC, convergent

recombination, antigen load, duration of the pMHC–

TCR interaction and the pMHC structural landscape

[10,11�,12]. However, the relative contribution of such

factors in shaping the TCR repertoire remains unclear.

Examples of TCR bias are observed in persistent viral

infections including Epstein-Barr virus (EBV) [13], cyto-

megalovirus (CMV) [14], human immunodeficiency virus

(HIV), SIV [15] and influenza [16,17]. As some of these

viruses represent a significant threat to human health,

understanding T-cell repertoire selection is important at a

therapeutic level for vaccine design and immunotherapy.

In addition, TCR bias has been reported in autoimmunity

as well as in lipid-based immunity. Recently the struc-

tural basis of biased TCR usage has begun to emerge, and

we review recent data in this field that encompasses

peptide and lipid-based recognition and discuss the

implications for biased TCR usage, MHC restriction

and immunity.


mailto:[email protected]

mailto:[email protected]

http://dx.doi.org/10.1016/j.coi.2007.12.001

120 Antigen Processing and Recognition

Figure 1

The TCR diversity is concentrated in the CDR3. (a) The crystal structure of the TCR ELS4 (a-chain in blue and the b-chain in pink) in complex

with EPLP/HLA-B*3501 (EPLP in maroon, the MHC heavy chain in grey and the b2m in green) and show how a TCR binds a pMHC. (b) The

CDR3a is composed of three residues coded by the V gene segment TRAV1-2*01 (orange), nine residues coded by the J gene segment

TRAJ6*01 (red) and one residue is the product of the random insertion/deletion in the junction region V-(N)-J (yellow). The CDR3b is coded

by the TRBV10-3*01 (purple), the TRBD1 (cyan) and the TRBJ1-5*01 (green). The TRBD1 includes the downstream V-(N1)-D junction region

and the upstream D-(N2)-J region, which are responsible for the high diversity by the random insertion/deletion, with N1 coding for A and

N2 for GTGD in this TCR. (c) The six CDRs loops interacting with the pMHC complex.

Structural overviewThe TCR is composed of two chains, a and b, both of

which comprise a variable domain that interacts with Ag,

and a constant domain that interacts with the CD3

complex [18]. The MHC molecule is also heterodimeric,

composed of either a heavy chain (hc) and b2 micro-

globulin for MHC-I or an a and a b chain for MHC-II

[18]. Antigenic peptides reside within the Ag-binding

cleft, which is bound by two long a-helices (a1 and a2)

(Figure 1c). There has been a number of TCR–pMHC

crystal structures determined to date permitting some

generalisations regarding TCR docking. Although the

basis of MHC-restriction remains unclear, a rough dock-

ing mode is preserved, in which the TCR Va domain is

positioned over the MHC a2-helix and the N-terminal

end of the peptide, whilst the TCR Vb domain contacts

the MHC a1-helix and the C-terminal end of the


peptide (Figure 1). Within this approximate framework,

either or both of the CDR3 loops can interact with the

peptide and also with the MHC. Likewise whilst the

CDR1 and CDR2 loops generally interact with the

MHC, they have also been observed to interact with

the peptide [19,20�]. Some of these TCR–pMHC com-

plexes utilize biased TCRs (see Table 1) and can there-

fore provide an understanding of how the antigenic

landscape leads to the selection of a biased T-cell

repertoire.

Three different types of TCR bias

There are a number of terms used in the literature to

describe biased TCR usage, including public, restricted,

limited, immunodominant, and for this review we use the

term TCR bias. TCR bias can be sub-divided into three

different operational types according to the degree of bias


TCR bias Gras et al. 121

Figure 2

An overview of the TCR-Ag-MHC complex structures that include biased TCRs. The TCR is represented in blue for the a-chain and in pink for

the b-chain, the MHC heavy chain (or the b-chain for MHC class II) is in grey and the b2M (or the a-chain for MHC class II) is in green. The

peptide is represented in stick conformation. All the complexes have been aligned by the a1–a2 domain of the MHC in order to show the

different docking angle for each complex. The structures represented are (a) LC13/FLR/HLA-B8, (b) SB27/LPEP/HLA-B*3508, (c)ELS4/EPLP/HLA-B*3501, (d) JM22/MP58–66/HLA-A2, (e) 172.10/MBP1-11/I-Au and (f) NKT15/a-GalCer/CD1d, respectively.

in Va/Vb and CDR3 usage. Type 1 bias consists of at least

one biased V region selection, but does not display con-

served CDR3 usage. The type 2 bias is defined by

sequence conservation within the CDR3 loop, and can

be characterised by the presence of sequence motifs; and

Type 3 TCR bias displays conserved Va and/or Vb usage

as well as conservation within the CDR3 loop [11�].

Table 1

Examples of TCR bias where structural data are available

Virus Epitope source Epitope MHC TCR–p

struc

(TCR n

EBV EBNA3 FLR193–201 HLA-B8 Yes (LC

EBNA1 HPVG407–417 HLA-B*3508 No

HLA-B*3501

BZLF1 LPEP52–64 HLA-B*3508 Yes (S

BZLF1 EPLP54–64 HLA-B*3501 Yes (EL

Influenza Matrix protein MP58–66 HLA-A2 Yes (JM

Nucleoprotein NP366–374 H2Db No

HIV p24 capsid KF11160–170 HLA-B*5703 No

Other Myelin basic protein MBP1–11 I-Au (class II) Yes (17

Lipid (marine sponge) aGalCer CD1d Yes (N


TCR bias and Epstein-Barr virus (EBV) infection

Our laboratories have been interested in understanding

the immune response and T-cell repertoire selection

against EBV, a persistent pathogen that infects more

than 90% of the human population. The immune

response is directed against a number of EBV antigens.

Examples of TCR bias, where structural data exists,

MHC

ture

ame)

TRAV TRBV Bias

type

pMHC

structure

TCR

structure

Reference

13) 26–2*01 7-8*03 3 Yes Yes [21�]

20 or 29 9 3 Yes No [24]

B27) 19 5–6 3 Yes No [26�]

6–1

7–2

20–1

27

28

S4) 1–2 10–3 3 Yes Yes [25]

22) No bias 19*01 3 No No [20�]

No bias 13–1 3 Yes No [17]

5 19 3 Yes No [16]

2.10) No bias 13–2 2 Yes No [31]

KT15) 10 25–1 2 Yes Yes [34��]



include responses against EBNA 1, EBNA3 and the

BZLF1 antigen.

(i)EBNA3 AgThe first structural correlates into biased TCR usage

were established in the LC13 TCR system, which

recognises the HLA-B*0801-restricted EBNA3 epitope,

FLRGRAYGL (termed FLR). The FLR-specific T-cell

response is characterised by biased Va and Vb usage

(TRAV26-2*01, TRAJ52*01, TRBV7-8*03, TRJB2-

7*01) as well as conservation in the CDR3 loops (type

3 bias) (Table 1). The LC13 TCR was shown to undergo

conformational changes in the CDR 1, 2 and 3 loops

upon binding the Ag, and focus on the P7-Tyr from the

FLR epitope [21�], which was previously shown to be a

Figure 3

Structural features of TCR–Ag–MHC complexes that include biased TCRs. Th

with the CDR1a and CDR2a loops in orange and the CDR3a loop in red. The b

CDR3b loop in green. The contacts between the TCR and the peptide are rep

are red. (a) The LC13/FLR/HLA-B8 complex reveals focusing of the TCR on P

the LC13 TCR, with vdw contacts made via both CDR1a Tyr31 and CDR3b

orthogonal docking mode for the SB27 TCR in order to accommodate the b

MHC a2-helix and a number of contacts are thus established between Va and

as a dashed red line). (c) For clarity, in the ELS4/EPLP/HLA-B*3501 complex

are shown. The conserved SGGS motif of the CDR3a loop acts to cover ov

CDR3b loop is responsible for pushing the peptide towards the a1-helix. (d) T

recognize a notch in the MP58–66 peptide (shown in orange). The JM22 TCR

loop (shown in green) to recognize a notch in the MP58–66/HLA-A2 complex

chain is selected by the MHC through a network of contacts established be

(shown in pale green). The Vb8.2 residues responsible for the conserved inter

shows the NKT15 receptor in a parallel docking mode recognizing a lipid Ag.

by the CDR1a loop (shown in orange) and the CDR3a loop (shown in red). The

with the CD1d molecule.


critical determinant (Figure 3a). An alanine-scanning

mutagenesis study on the LC13 TCR also revealed that

the CDR3 loops dictate the energetics of the interaction,

with the CDR3a and CDR3b loops primarily

responsible for interacting with HLA-B8 and the FLR

epitope respectively [22,23]. Accordingly TCR bias is

largely driven by interactions mediated via the non-

germline encoded CDR3 regions.

(ii)EBNA1 AgAn 11-mer HPVGEADYFEY epitope from the nuclear

protein EBNA1, presented by HLA-B*3508 or HLA-

B*3501, selects T-cells with a biased TCR repertoire

using TRBV9 [24]. There was also sequence

conservation in the CDR3b and CDR3a of these T-

cell clones (Table 1). Interestingly, the Va usage is

e colour coding is the same as with Figure 2. The a-chain is in pale blue

-chain is in pale pink with the CDR1b and CDR2b loops in purple and the

resented by a blue dash line and the one between the TCR and the MHC

7-Tyr of the FLR peptide (in blue stick format). The P7-Tyr is enveloped by

Tyr100 residues. (b) The SB27/LPEP/HLA-B*3508 structure shows an

ulged 13-mer LPEP peptide. The alpha chain is tilted towards the

the a2-helix, whereas the b-chain primarily contacts the peptide (shown

only the CDR3a and CDR3b loops, each containing a conserved motif,

er the N-terminal part of the peptide. The conserved TGD motif of the

he JM22/MP58–66/HLA-A2 structure reveals how the JM22 TCR is able to

uses a biased Vb chain with a conserved ‘RS’ motif in the CDR3b

. (e) The 172.10/MBP1-11/I-Au structure reveals how the biased Vb8.2

tween the CDR1b and CDR2b loops (shown in purple) and the a1-helix

action are shown in stick format. (f) The NKT15/a-GalCer/CD1d structure

The biased Va chain is responsible for the majority of the contacts, made

biased Vb11 chain makes contact via the CDR2b loop (shown in purple)



dictated by the HLA type of the virus carrier, being

biased towards TRAV20 or TRAV29 in HLA-B*3501+ or

HLA-B*3508+ individuals respectively. These two HLA

molecules differ by only one amino acid at position 156,

(Arg or Leu in B*3508 or B*3501, respectively) and the

structures of these binary complexes reveal the HPVG

epitope to be highly mobile in B*3501 yet well ordered

in B*3508 [24]. This difference of Ag mobility appears to

be responsible for the biased Va chain selection,

suggesting that biased Vb usage is directed by

interactions with the MHC.

(iii)BZLF1 AgTypically MHC-I molecules bind epitopes of 8–10

residues in length, but approximately 5% of epitopes

can be more than 10 amino acids long and such epitopes

typically bulge centrally from the Ag-binding cleft.

These atypical pMHC landscapes have been associated

with biased TCR usage [24,25,26�]. Tynan et al. have

solved the structure of a TCR, SB27, in complex with a

13-mer peptide (termed LPEP) from the BZLF1 antigen

restricted to HLA-B*3508 [26�] (Figure 2b). The T-cell

response (of which the SB27 TCR was the archetype) to

this epitope exhibits biased a-chain usage (TRAV19 and

TRAJ34), and a preference for some Vb chains (TRBV5-

6, TRBV6-1, TRBV7-2, TRBV20-1, TRBV27 or

TRBV28) [27�] (Table 1). Interestingly, the SB27 TCR

docked orthogonally to accommodate the bulged epitope

(Figure 2b), with the Va domain tilted forward towards

the a2-helix, and as a consequence the Vb domain

formed few interaction with the MHC, and played a

more prominent role in interacting with the peptide

(Figure 3b). The SB27 TCR made many fewer contacts

with the MHC in comparison to TCRs interacting with

canonical length epitopes and as such this ternary

complex provided insight into the minimal basis of

MHC-restriction. Collectively, the CDR1a, CDR2a and

CDR3a loops provided the main contacts with HLA

B*3508, thereby explaining the biased Va usage,

whereas the CDR1b loop played a prominent role in

interacting with the peptide, thereby underscoring the

preferential Vb usage.

The ELS4 TCR is also directed against a bulged epitope

from the BZLF1 Ag (EPLP), but is restricted to HLA-

B*3501 [25]. The T-cell response to this Ag is charac-

terised by TRAV1-2/TRAJ6 and TRBV10-3/TRBJ1-5

usage [28]. Moreover, both the CDR3a and CDR3b loops

contain 9 residues with the conserved motifs of ‘SGGS’ or

‘TGD’, respectively (Table 1 and Figure 3c). Interest-

ingly, whilst conformational changes upon TCR–pMHC

ligation are generally observed for TCRs, in this case the

ELS4 TCR remained relatively rigid upon binding.

Instead, the EPLP peptide was ‘bulldozed’ upon ELS4

ligation, enabling the TCR to make a large number of

contacts with HLA-B*3501. The movement in the pep-

tide is quite marked, and the conserved ‘96TGD98’ motif


of the CDR3b loop pushed the peptide towards the a1-

helix, whilst the CDR3a ‘95SGGS98’ motif is largely

involved in interacting with HLA-B*3501 (Figure 3c)

as well as interacting with the P1 peptide residue

(Figure 3c).

TCR bias and influenza A infection

Influenza infection, both in animal models and within

the human population, can also generate a biased TCR

response against defined antigens. A biased TCR

response against the HLA-A2-restricted influenza matrix

protein peptide GILGFVFTL (termed MP58–66) has

been shown [20�]. The canonical TCR, JM22, exhibits

Vb17 (TRBV19*01) usage and a highly conserved

CDR3b sequence ‘98RS99’ (Figure 3d). The biased Vb

selection was reflected in its dominant role in interaction

with the Ag. The MP58–66 epitope was termed a fea-

tureless epitope, and this permitted the insertion of the

highly conserved Arg98 of the CDR3b loop between the

peptide and the HLA-A2 a2-helix (Figure 3d), thereby

providing a basis for the biased TCR usage in this

instance.

This observation led to the hypothesis that a featureless

pMHC landscape was a mechanism that selects a biased

TCR usage. To examine this, Turner and colleagues

examined T-cell repertoire selection in a murine model

of influenza against a featureless NP366–374 epitope and a

more featured PA224–233 epitope. The TCR repertoire

specific for the nucleoprotein peptide NP366–374 exhibits

TCR bias (TRBV13-1-TRBD1-TRBJ2-2) whereas the

response against the more featured PA epitope was more

diverse [17,29]. Interestingly, generating a more feature-

less PA epitope via genetic engineering resulted in a more

biased TCR repertoire [17].

TCR bias and human immunodeficiency virus (HIV)

infection

HLA-B57 has been associated with slower disease pro-

gression in HIV infection, and interestingly, functional

differences in HIV immunity are observed in individuals

who are HLA-B*5701+ or HLA-B*5703+ that respond to

the same HIV determinant. One of the immunodominant

epitopes in HLA-B57+ individuals from HIV is the KF11

peptide (KAFSPEVIPMF) derived from the p24 capsid

protein [16]. The KF11 response selected a biased T-cell

repertoire, displaying TRAV5 and TRBV19 usage and

moreover the TCRs share common CDR3a and CDR3b

sequences. The structure of KF11 in complex with HLA-

B*5703 also revealed a bulged conformation for this

peptide [30]. The authors have solved the structure of

a shorter epitope version (called KF8), which binds the

MHC in a very different conformation. Interestingly the

T-cell clones specific for the KF8 peptide were partially

cross-reactive to the KF11 peptide whereas that the KF11

T-cell specific clones do not show any cross-reactivity to

the KF8 peptide. These data suggest a highly specific



binding mode by the biased TCR of the bulged KF11

peptide.

TCR bias and autoimmunity

Maynard et al. determined the structure of the 172.10

TCR in complex with a myelin basic protein MBP1–11

peptide bound to the I-Au MHC class II molecule [31]

(Figure 2e). Their study of murine experimental auto-

immune encephalomyelitis (EAE) indicated that the T-

cell response to MBP1–11 exhibited highly biased TCR

Vb8.2 gene usage (TRBV13-2 in IMGT database). The

biased Vb chain dominated the interaction with the

pMHC, with CDR1b and CDR2b interacting with the

a1-helix (Figure 3e). Interestingly the mode of docking of

Vb8.2 of the 172.10 TCR is similar to the docking

strategies used by other TCRs utilizing Vb8.2

[32,33��], including specific interactions between the

TCR and the MHC. Thus these studies provide evidence

for preferred sets of interactions between particular TCR

and pMHC molecules.

TCR bias and lipid presentation

In addition to peptide Ags, lipid-based Ags can also lead

to biased TCR usage, as in the case of the semi-invariant

TCR expressed on NKT cells, which recognises CD1d-

Ag complexes. The archetypal human NKT TCR is

characterised by invariant a-chain usage Va24-Ja18

(TRAV10-TRAJ18) and Vb11 (TRBV25-1) bias, but

lacks CDR3b conservation (Table 1). Recently the struc-

ture of the NKT TCR in complex with CD1d-aGalCer

has been determined, providing a structural basis for the

preferred Va/Vb usage (Figure 2f) [34��]. The invariant

Va usage is consistent with dominant Va domain con-

tacts, and contributes two thirds of the buried surface area

of the TCR at the interface with the CD1d-a-GalCer

complex. The a-GalCer protruded minimally over the

CD1d groove; only the glycosyl head group is solvent

exposed to interact with the NKT TCR. The invariant

Ja18 usage correlates well with the CDR3a loop making

extensive contacts with the CD1d a1 helix, the a2 helix

and a-GalCer whereas the CDR1a loop interacted solely

with the lipid Ag (Figure 3f). The Vb11 bias is reflected in

key contacts established between CDR2b and CD1d.

DiscussionWhilst TCR diversity is clearly a key facet of protective

immunity, TCR bias also represents an important factor

in immunity, with examples of TCR bias occurring in

antiviral immunity, alloreactivity and auto-immunity.

The parameters leading to generation of TCR bias have

begun to emerge, and include the need to recognize

atypical pMHC landscapes, such as featureless and

bulged epitopes. Structural studies on biased TCR usage

have been informative in not only understanding the

underlying basis of TCR bias, but have also shed pro-

found insight into the fundamental basis of TCR–pMHC

interactions. For example the SB27 TCR minimally


contacted the MHC, and suggested that three positions

on the MHC molecule (residues 65, 69 and 155) are the

minimal requirements for MHC-restriction [26�]. Sim-

ilarly, the study on murine Vb8.2-biased TCRs have

revealed ‘interaction codons’, namely patterns of recog-

nition between TCR and MHC [33��]. Interestingly,

Vb8.2-biased TCRs also interact with CD1d–Ag com-

plexes, and the NKT TCR also represents an example of

biased TCR usage against a relatively featureless CD1d-

Ag landscape. For the TCR to recognize such peptide-

based and lipid-based Ags, docking strategies ranging

from parallel to orthogonal have been observed, high-

lighting the adaptability of the TCR. Subtle changes in

the peptide ligand, such as in the case of viral escape, can

have a profound effect on the T-cell repertoire, and it is

important that we understand the link between the

pMHC landscape and TCR in order to optimize immu-

notherapeutic approaches to treat the plethora of life-

threatening ailments involving T cells.

AcknowledgementsThe authors would like to thank members of their laboratories forcontributions towards these studies. The Australian Research Council(ARC), the Anti-Cancer Council and the National Health and MedicalResearch Council of Australia (NHMRC) supported this research. SB issupported by a NHMRC Senior Research Fellowship and JR by an ARCFederation Fellowship.

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20.�

Stewart-Jones GB, McMichael AJ, Bell JI, Stuart DI, Jones EY: Astructural basis for immunodominant human T-cell receptorrecognition. Nat Immunol 2003, 4:657-663.

Represents one of the 1st structural reports of biased TCR interactionswith cognate receptor.

21.�

Kjer-Nielsen L, Clements CS, Purcell AW, Brooks AG,Whisstock JC, Burrows SR, McCluskey J, Rossjohn J: Astructural basis for the selection of dominant alphabetaT-cell receptors in antiviral immunity. Immunity 2003, 18:53-64.

Represents one of the 1st structural reports of biased TCR interactionswith cognate receptor.

22. Borg NA, Ely LK, Beddoe T, Macdonald WA, Reid HH,Clements CS, Purcell AW, Kjer-Nielsen L, Miles JJ, Burrows SRet al.: The CDR3 regions of an immunodominant T-cellreceptor dictate the ‘energetic landscape’ of peptide-MHCrecognition. Nat Immunol 2005, 6:171-180.

23. Ely LK, Beddoe T, Clements CS, Matthews JM, Purcell AW, Kjer-Nielsen L, McCluskey J, Rossjohn J: Disparate thermodynamicsgoverning T-cell receptor-MHC-I interactions implicate


extrinsic factors in guiding MHC restriction. Proc Natl Acad SciU S A 2006, 103:6641-6646.

24. Miles JJ, Borg NA, Brennan RM, Tynan FE, Kjer-Nielsen L,Silins SL, Bell MJ, Burrows JM, McCluskey J, Rossjohn J et al.:TCR alpha genes direct MHC restriction in the potent humanT-cell response to a class I-bound viral epitope. J Immunol2006, 177:6804-6814.

25. Tynan FE, Reid HH, Kjer-Nielsen L, Miles JJ, Wilce MC,Kostenko L, Borg NA, Williamson NA, Beddoe T, Purcell AW et al.:A T-cell receptor flattens a bulged antigenic peptidepresented by a major histocompatibility complex class Imolecule. Nat Immunol 2007, 8:268-276.

26.�

Tynan FE, Burrows SR, Buckle AM, Clements CS, Borg NA,Miles JJ, Beddoe T, Whisstock JC, Wilce MC, Silins SL et al.: T-cell receptor recognition of a ’super-bulged’ majorhistocompatibility complex class I-bound peptide. NatImmunol 2005, 6:1114-1122.

Describes how a biased TCRs interacts with a bulged epitope.

27.�

Tynan FE, Borg NA, Miles JJ, Beddoe T, El-Hassen D, Silins SL,van Zuylen WJ, Purcell AW, Kjer-Nielsen L, McCluskey J et al.:High resolution structures of highly bulged viral epitopesbound to major histocompatibility complex class I.Implications for T-cell receptor engagement and T-cellimmunodominance. J Biol Chem 2005, 280:23900-23909.

Describes how a biased TCRs interacts with a bulged epitope.

28. Miles JJ, Elhassen D, Borg NA, Silins SL, Tynan FE, Burrows JM,Purcell AW, Kjer-Nielsen L, Rossjohn J, Burrows SR et al.: CTLrecognition of a bulged viral peptide involves biased TCRselection. J Immunol 2005, 175:3826-3834.

29. Zhong W, Dixit SB, Mallis RJ, Arthanari H, Lugovskoy AA,Beveridge DL, Wagner G, Reinherz EL: CTL recognition of aprotective immunodominant influenza A virus nucleoproteinepitope utilizes a highly restricted Vbeta but diverse Valpharepertoire: functional and structural implications. J Mol Biol2007, 372:535-548.

30. Stewart-Jones GB, Gillespie G, Overton IM, Kaul R, Roche P,McMichael AJ, Rowland-Jones S, Jones EY: Structures of threeHIV-1 HLA-B*5703-peptide complexes and identification ofrelated HLAs potentially associated with long-termnonprogression. J Immunol 2005, 175:2459-2468.

31. Maynard J, Petersson K, Wilson DH, Adams EJ, Blondelle SE,Boulanger MJ, Wilson DB, Garcia KC: Structure of anautoimmune T-cell receptor complexed with class II peptide-MHC: insights into MHC bias and antigen specificity. Immunity2005, 22:81-92.

32. Reinherz EL, Tan K, Tang L, Kern P, Liu J, Xiong Y, Hussey RE,Smolyar A, Hare B, Zhang R et al.: The crystal structure of a T-cell receptor in complex with peptide and MHC class II.Science 1999, 286:1913-1921.

33.��

Feng D, Bond CJ, Ely LK, Maynard J, Garcia KC: Structuralevidence for a germline-encoded T-cell receptor-majorhistocompatibility complex interaction ‘codon’. Nat Immunol2007, 8:975-983.

A detailed study examining Vb8.2 usage and demonstrating germlineencoded TCR residues (interaction ‘‘codons’’) that always interact withMHC.

34.��

Borg NA, Wun KS, Kjer-Nielsen L, Wilce MC, Pellicci DG, Koh R,Besra GS, Bharadwaj M, Godfrey DI, McCluskey J et al.: CD1d-lipid-antigen recognition by the semi-invariant NKT T-cellreceptor. Nature 2007, 448:44-49.

Provides insight into glycolipid-mediated recognition and describes theinvariant Va-Ja usage in interacting with CD1d.


T-cell receptor bias and immunity

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