CTL Recognition of a Bulged Viral Peptide Involves Biased TCR Selection

Miles, John J.; Elhassen, Diah; Borg, Natalie A.; Silins, Sharon L.; Tynan, Fleur Elizabeth; Burrows, Jacqueline M.; Purcell, Anthony W.; Kjer‐Nielsen, Lars; Rossjohn, Jamie; Burrows, Scott R.; McCluskey, James

doi:10.4049/jimmunol.175.6.3826

Cited by 94 publications

(83 citation statements)

References 59 publications

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“…Although several examples of TCR bias in human CD8 + T cells during viral infection have been reported (39)(40)(41)(42)(43), to our knowledge TCR bias has never been shown for human CD4 + T cells during viral infections. In this study, we have identified five brain-derived CD4 + TCCs specific for VP1 34 peptide with almost identical TCR a-and b-chains but different CDR3 regions and the associated J segments.…”

Section: Virus-specific Cd8mentioning

confidence: 91%

“…TCR bias can result from the selection of a single TRAV and/or TRBV region but little conservation in the CDR3 regions or can also involve conserved amino acids in CDR3 sequences (37). Several examples of TCR bias in human CD8 + T cells during persistent but also acute viral infections have been reported (39)(40)(41)(42)(43). TCR bias can confer an advantage in virusspecific immune responses by selecting virus-specific CD8 + T cells with higher avidity (41,44) and with optimal TCR structural characteristics for a given peptide-MHC complex topography (45)(46)(47).…”

Section: Irus-specific Cd4mentioning

confidence: 99%

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TCR Bias and HLA Cross-Restriction Are Strategies of Human Brain-Infiltrating JC Virus-Specific CD4+ T Cells during Viral Infection

Yousef

Planas

Chakroun

et al. 2012

The Journal of Immunology

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Virus-specific CD4+ T cells play a central role in control of viral pathogens including JC polyoma virus (JCV) infection. JCV is a ubiquitous small DNA virus that leads to persistent infection of humans with no clinical consequences. However, under circumstances of immunocompromise, it is able to cause an opportunistic and often fatal infection of the brain called progressive multifocal leukoencephalopathy (PML). PML has emerged as a serious adverse event in multiple sclerosis patients treated with the anti–VLA-4 mAb natalizumab, which selectively inhibits cell migration across the blood–brain barrier and the gut’s vascular endothelium thus compromising immune surveillance in the CNS and gut. In a multiple sclerosis patient who developed PML under natalizumab treatment and a vigorous immune response against JCV after Ab washout, we had the unique opportunity to characterize in detail JCV-specific CD4+ T cell clones from the infected tissue during acute viral infection. The in-depth analysis of 14 brain-infiltrating, JCV-specific CD4+ T cell clones demonstrated that these cells use an unexpectedly broad spectrum of different strategies to mount an efficient JCV-specific immune response including TCR bias, HLA cross-restriction that increases avidity and influences in vivo expansion, and a combination of Th1 and Th1-2 functional phenotypes. The level of combinatorial diversity in TCR– and HLA–peptide interactions used by brain-infiltrating, JCV-specific CD4+ T cells has not, to our knowledge, been reported before in humans for other viral infections and confirms the exceptional plasticity that characterizes virus-specific immune responses.

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Section: Virus-specific Cd8mentioning

confidence: 91%

Section: Irus-specific Cd4mentioning

confidence: 99%

TCR Bias and HLA Cross-Restriction Are Strategies of Human Brain-Infiltrating JC Virus-Specific CD4+ T Cells during Viral Infection

Yousef

Planas

Chakroun

et al. 2012

The Journal of Immunology

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“…Firstly, we examined CTL recognition of HLA-B*0801 FLR by 12 different T cell clones, as well as two CTL clones directed against the HLA-B*0801-restricted RAKFKQLL (referred to as RAK) epitope (20). Secondly, we examined the effect of the mutations on a number of clones targeted to one of four HLA-B*3508-restricted viral epitopes of different length: a 13-mer (LPEPLPQGQLTAY), a 12-mer (CPSQEPMSIYVY), an 11-mer (HPVGEADYFEY), or a 10-mer (APQPAPENAY) (21)(22)(23)(24).…”

Section: Resultsmentioning

confidence: 99%

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.

Self Cite

107

122

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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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“…Public TCR sequences (i.e., identical TCR amino acid sequences observed in many MHC-matched individuals) have been observed in many studies of the CD8 ϩ T cell responses to specific CMV epitopes (9, 11, 16 -21) and EBV epitopes (22)(23)(24)(25)(26)(27)(28)(29). Such public TCRs are unexpected, because the potential diversity of the thymic TCR repertoire (Ͼ10 15 ) (1) greatly exceeds the estimated diversity of the peripheral TCR repertoire (ϳ10 7 ) (2).…”

mentioning

confidence: 99%

TCR β-Chain Sharing in Human CD8+ T Cell Responses to Cytomegalovirus and EBV

Venturi

Chin

Asher

et al. 2008

The Journal of Immunology

105

133

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The CD8؉ TCR repertoires specific for many immunogenic epitopes of CMV and EBV are dominated by a few TCR clonotypes and involve public TCRs that are shared between many MHC-matched individuals. In previous studies, we demonstrated that the observed sharing of epitope-specific TCR␤ chains between individuals is strongly associated with TCR␤ production frequency, and that a process of convergent recombination facilitates the more efficient production of some TCR␤ sequences. In this study, we analyzed a total of 2836 TCR␤ sequences from 23 CMV-infected and 10 EBV-infected individuals to investigate the factors that influence the sharing of TCR␤ sequences in the CD8 ؉ T cell responses to two immunodominant HLA-A*0201-restricted epitopes from these viruses. The most shared TCR␤ amino acid sequences were found to have two features that indicate efficient TCR␤ production, as follows: 1) they required fewer nucleotide additions, and 2) they were encoded by a greater variety of nucleotide sequences. We used simulations of random V(D)J recombination to demonstrate that the in silico TCR␤ production frequency was predictive of the extent to which both TCR␤ nucleotide and amino acid sequences were shared in vivo. These results suggest that TCR␤ production frequency plays an important role in the interindividual sharing of TCR␤ sequences within CD8 ؉ T cell responses specific for CMV and EBV.

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CTL Recognition of a Bulged Viral Peptide Involves Biased TCR Selection

Cited by 94 publications

References 59 publications

TCR Bias and HLA Cross-Restriction Are Strategies of Human Brain-Infiltrating JC Virus-Specific CD4+ T Cells during Viral Infection

TCR Bias and HLA Cross-Restriction Are Strategies of Human Brain-Infiltrating JC Virus-Specific CD4+ T Cells during Viral Infection

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

TCR β-Chain Sharing in Human CD8+ T Cell Responses to Cytomegalovirus and EBV

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