The CDR3 regions of an immunodominant T cell receptor dictate the 'energetic landscape' of peptide-MHC recognition

Borg, Natalie A.; Ely, Lauren Kate; Beddoe, Travis; Macdonald, W.A.; Reid, Hugh Harrington; Clements, Craig Steven; Purcell, Anthony W.; Kjer‐Nielsen, Lars; Miles, John J.; Burrows, Scott R.; McCluskey, James; Rossjohn, Jamie

doi:10.1038/ni1155

Cited by 171 publications

(155 citation statements)

References 56 publications

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“…Whereas the TCR-MHC contacts are typically extensive, binding studies have shown that these interactions are governed by "energetic hotspots" (10,11). Consistent with this finding, our analyses showed that three (65, 69, and 155) positions, on the MHC were invariably contacted in essentially all TCR-pMHC-I systems reported to date (14).…”

Section: Discussionsupporting

confidence: 78%

“…Namely, the current TCR-pMHC-I structural database demonstrates that the germline-encoded CDR1/2 loops frequently play an important role in contacting the peptide, but perhaps more critically, the CDR3 loops can and do play a principal role in contacting the MHC-I. This interpretation is further supported by mutagenesis experiments that demonstrated an important energetic role for the CDR3 loops in contacting the MHC-I and for the CDR1/2 loops in contacting the peptide (8,11).…”

Section: Discussionsupporting

confidence: 60%

“…Consistent with this perspective, mutations in the germline-encoded CDR2β region within Vβ8.2 + TCRs impact negatively on thymic selection reflecting a central role for these interactions in MHC recognition (9). However, associated biophysical, thermodynamic, and mutational studies have also shown that the relative energetic contributions from the CDR loops can vary between the various TCR-pMHC systems (10,11). Accordingly, it is also considered that extrinsic factors, such as the CD8 coreceptor, play a principal role in MHC restriction, which is consistent with recent observations from CD8 − CD4 − mice (12,13).…”

mentioning

confidence: 79%

“…All surface plasmon resonance experiments were conducted at 25°C on the BIAcore 3000 essentially as previously described (11). All experiments were conducted in duplicate or quadruplicate.…”

Section: Methodsmentioning

confidence: 99%

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Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability

Burrows

Chen

Archbold

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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αβ T cell receptors (TCRs) are genetically restricted to corecognize peptide antigens bound to self-major histocompatibility complex (pMHC) molecules; however, the basis for this MHC specificity remains unclear. Despite the current dogma, evaluation of the TCR-pMHC-I structural database shows that the nongermline-encoded complementaritydetermining region (CDR)-3 loops often contact the MHC-I, and the germline-encoded CDR1 and -2 loops frequently participate in peptide-mediated interactions. Nevertheless, different TCRs adopt a roughly conserved docking mode over the pMHC-I, in which three MHC-I residues (65, 69, and 155) are invariably contacted by the TCR in one way or another. Nonetheless, the impact of mutations at these three positions, either individually or together, was not uniformly detrimental to TCR recognition of pHLA-B*0801 or pHLA-B*3508. Moreover, when TCR-pMHC-I recognition was impaired, this could be partially restored by expression of the CD8 coreceptor. The structure of a TCR-pMHC-I complex in which these three (65, 69, and 155) MHC-I positions were all mutated resulted in shifting of the TCR footprint relative to the cognate complex and formation of compensatory interactions. Collectively, our findings reveal the inherent adaptability of the TCR in maintaining peptide recognition while accommodating changes to the central docking site on the pMHC-I.MHC restriction | T cell recognition | structural immunology | immunogenetics D uring thymic selection αβ T cell receptors (TCRs) are selected for weak reactivity with one or more self-peptides in complex with self-MHC (major histocompatibility complex), resulting in mature T cells being restricted to recognize processed peptides only when they are presented by self-MHC molecules (1). The exquisite specificity of TCR-pMHC binding must address the highly polymorphic nature of the MHC and variable peptide cargo. The antigen-recognition site of the TCR is made up of six complementarity-determining regions (CDRs), three each from the α and β chains (2). Currently, it is postulated that the CDR1 and 2 loops underpin the specificity or "bias" toward the MHC, whereas the CDR3 loops recognize the diverse range of bound peptides (3-5). Recent studies support the view that the T cell repertoire is intrinsically biased toward the MHC through contacts mediated by conserved TCR Vα and Vβ residues (6). However, the factors governing MHC restriction, a central paradigm of antigen-specific T cell immunity, remain unclear.Presumably as a consequence of the polymorphic pMHC landscape, and the inherent diversity of the responding T cell repertoire, structural studies have shown that the TCR engages the pMHC-I and pMHC-II surfaces in a range of different docking modes (2). Nevertheless, conserved pairwise interactions between closely related Vβ8.2 + TCRs and pMHC-II molecules were identified, leading to the concept that there are defined interaction "motifs" or "codons" between the Vα and/or Vβ domains of a TCR and a given MHC allotype (3,(6)(7)(8). Central to the "int...

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Section: Discussionsupporting

confidence: 78%

Section: Discussionsupporting

confidence: 60%

mentioning

confidence: 79%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability

Burrows

Chen

Archbold

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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107

122

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“…Gene rearrangement of different V, D, J and C regions leads to the assembly of highly diverse receptors with varying lengths. 21 An increased proportion of T cells with a restricted CDR-3 TCR-Vb nucleotide length, which is representative of clonal T-cell expansion, is known as 'TCR-Vb-repertoire skewing'. [22][23][24][25] In normal T-cell homeostasis, a limited number of clones undergo periodic expansion in response to foreign antigens.…”

Section: Introductionmentioning

confidence: 99%

Prevalence and clinical association of clonal T-cell expansions in Myelodysplastic Syndrome

et al. 2007

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Selected patients with Myelodysplastic Syndromes (MDS) are responsive to immunosuppressive therapy, suggesting that hematopoietic suppressive T cells have a pathogenic role in ineffective hematopoiesis. We assessed T-cell receptor (TCR) clonality through combined flow cytometry and molecular analysis of the complementarity determining region (CDR)-3 of the T-cell receptor-Vb gene. We identified clonal T cells in 50% of MDS patients (n ¼ 52) compared to 5% of age-matched normal controls (n ¼ 20). The presence of T-cell clones was not associated with features linked previously to immunosuppression response, including WHO diagnostic category, karyotype, marrow cellularity, IPSS category, sex or age p60. Using flow cytometry to identify expanded Vb-families, we found that T cells showed greater expansion in the bone marrow compared with peripheral blood, and were characterized as CD8 þ /CD57 þ /CD28 À effector T cells. Expanded effector T cell were CD62L negative and expressed the natural killer C-lectinfamily receptor NKG2D and CD244 (2B4). We conclude that clonal T-cell expansion is common among all MDS prognostic subgroups.

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Comparative analysis of CDR3 regions in paired human αβ CD8 T cells

Shi

Lü

et al. 2019

FEBS Open Bio

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The majority of human CD8 cytotoxic T lymphocytes express αβ T‐cell receptors that recognize peptide–MHC class I complexes. Considerable attention has been devoted to TCR β repertoires, but study of TCR α chains has been limited. To gain a better understanding of the features of CDR3α and CDR3β in paired samples, we comprehensively analyzed 776 unique paired αβ TCR CDR3 regions in this study. We found that (I) the CDR3 length among paired αβ TCRs had a fairly narrow distribution due to random assortment of CDR3 length in alpha and beta chains; (II) nucleotide deletions among CDR3 regions were positively correlated with insertions in both α and β TCRs; (III) the CDR3 loops of both α and β chains contained an abundance of charged/polar residues and the CDR3 base regions contained a conserved motif; and (IV) the occurrence of Gly was CDR3 length‐ and position‐dependent in both chains, whereas the frequency of Ser at positions 106 and 107 was positively correlated with CDR3 length in TCR β. Overall, the amino acids in CDR3 loop regions were significantly different between TCR α and β, which suggests a distinct role for each chain in the recognition of antigen–MHC complexes. Here, we have provided detailed information on CDR3 in paired TCRs expressed on human CD8+ T cells and established the basis of a reference set for αβ TCR repertoires in healthy humans.

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The CDR3 regions of an immunodominant T cell receptor dictate the 'energetic landscape' of peptide-MHC recognition

Cited by 171 publications

References 56 publications

Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability

Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability

Prevalence and clinical association of clonal T-cell expansions in Myelodysplastic Syndrome

Comparative analysis of CDR3 regions in paired human αβ CD8 T cells

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