Public clonotype usage identifies protective Gag-specific CD8+ T cell responses in SIV infection

Price, David A.; Asher, Tedi E.; Wilson, Nancy A.; Nason, Martha; Brenchley, Jason M.; Metzler, Ian S.; Venturi, Vanessa; Gostick, Emma; Chattopadhyay, Pratip K.; Roederer, Mario; Davenport, Miles P.; Watkins, David I.; Douek, Daniel C.

doi:10.1084/jem.20081127

Cited by 140 publications

(165 citation statements)

References 63 publications

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“…Different studies have also suggested that the structural constraints/mechanisms of the TCR-pMHC interaction (12,13,43,44) and the endogenous selection of T cells (45) might play an important role in the regulation of the level of TCR diversity. With regard to the biological relevance, it has recently been reported that the number of public clonotypes within CD8 T cells responding to an epitope known as protective in SIV infection (46) was correlated with a better outcome of virus infection (47). Of note, we have also identified two novel public clonotypes in response to EBV RAKFKQLL and EBV GLCTLVAML .…”

Section: Discussionmentioning

confidence: 58%

Large TCR Diversity of Virus-Specific CD8 T Cells Provides the Mechanistic Basis for Massive TCR Renewal after Antigen Exposure

Miconnet

Marrau

Farina

et al. 2011

The Journal of Immunology

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Ex vivo analysis of virus-specific CD8 T cell populations by anchored PCR has shown that the CD8 TCR repertoire was less oligoclonal (seven to nine clonotypes per individual epitope) than previously thought. In the current study, TCR diversity was investigated by assessing both the overall TCR β-chain variable regions usage as well as the CDR3 regions in ex vivo-isolated CMV- and EBV-specific CD8 T cells from 27 healthy donors. The average number of clonotypes specific to most single viral epitopes comprised between 14 and 77. Changes in the CD8 TCR repertoire were also longitudinally assessed under conditions of HIV-1 chronic infection (i.e., in patients with suppressed virus replication and after treatment interruption and Ag re-exposure). The results showed that a large renewal (≤80%) of the TRB repertoire occurred after Ag re-exposure and was eventually associated with an increased T cell recognition functional avidity. These results demonstrate that the global CD8 TCR repertoire is much more diverse (≤9-fold) than previously estimated and provide the mechanistic basis for supporting massive repertoire renewal during chronic virus infection and Ag re-exposure.

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Section: Discussionmentioning

confidence: 58%

Large TCR Diversity of Virus-Specific CD8 T Cells Provides the Mechanistic Basis for Massive TCR Renewal after Antigen Exposure

Miconnet

Marrau

Farina

et al. 2011

The Journal of Immunology

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“…In contrast, a more clonotypically diverse and protective CD8 + T-cell response specific for the biologically constrained Gag CM9/Mamu-A*01 epitope emerges marginally later. The degree of protection conferred by this response is predicted by the number of initially recruited public clonotypes, which presumably are mobilized more rapidly due to higher precursor frequencies within the naïve repertoire to control viral replication and mitigate the ensuing pathological consequences (21). Our data provide a molecular basis for the generation and selection of these biologically important CD8 + T-cell clonotypes, with attendant implications for T cell-based immune interventions.…”

Section: A G T G C a G G G A A C T A T A G T G C G G G A A A C T A T mentioning

confidence: 98%

Convergent recombination shapes the clonotypic landscape of the naïve T-cell repertoire

Quigley

Greenaway

Venturi

et al. 2010

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

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125

127

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Adaptive T-cell immunity relies on the recruitment of antigenspecific clonotypes, each defined by the expression of a distinct T-cell receptor (TCR), from an array of naïve T-cell precursors. Despite the enormous clonotypic diversity that resides within the naïve T-cell pool, interindividual sharing of TCR sequences has been observed within mobilized T-cell responses specific for certain peptide-major histocompatibility complex (pMHC) antigens. The mechanisms that underlie this phenomenon have not been fully elucidated, however. A mechanism of convergent recombination has been proposed to account for the occurrence of shared, or "public," TCRs in specific memory T-cell populations. According to this model, TCR sharing between individuals is directly related to TCR production frequency; this, in turn, is determined on a probabilistic basis by the relative generation efficiency of particular nucleotide and amino acid sequences during the recombination process. Here, we tested the key predictions of convergent recombination in a comprehensive evaluation of the naïve CD8 + TCRβ repertoire in mice. Within defined segments of the naïve CD8 + T-cell repertoire, TCRβ sequences with convergent features were (i) present at higher copy numbers within individual mice and (ii) shared between individual mice. Thus, the naïve CD8 + T-cell repertoire is not flat, but comprises a hierarchy of recurrence rates for individual clonotypes that is determined by relative production frequencies. These findings provide a framework for understanding the early mobilization of public CD8 + T-cell clonotypes, which can exert profound biological effects during acute infectious processes.

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“…In addition, examples of public TCRs were extensively observed in non-human primates and mice [25]. Notably, public TCRs were shown to lead to favorable biological outcomes in acute SIV infection [26]. Studies of HIV-infected individuals with a long- term non-progressive disease have also revealed shared TCRs that display effective cross-recognition of epitope variants [9,[27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Determinants of public T cell responses

et al. 2012

Cell Res

118

112

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Historically, sharing T cell receptors (TCRs) between individuals has been speculated to be impossible, considering the dramatic discrepancy between the potential enormity of the TCR repertoire and the limited number of T cells generated in each individual. However, public T cell response, in which multiple individuals share identical TCRs in responding to a same antigenic epitope, has been extensively observed in a variety of immune responses across many species. Public T cell responses enable individuals within a population to generate similar antigen-specific TCRs against certain ubiquitous pathogens, leading to favorable biological outcomes. However, the relatively concentrated feature of TCR repertoire may limit T cell response in a population to some other pathogens. It could be a great benefit for human health if public T cell responses can be manipulated. Therefore, the mechanistic insight of public TCR generation is important to know. Recently, high-throughput DNA sequencing has revolutionized the study of immune receptor repertoires, which allows a much better understanding of the factors that determine the overlap of TCR repertoire among individuals. Here, we summarize the current knowledge on public T-cell response and discuss future challenges in this field.

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Public clonotype usage identifies protective Gag-specific CD8+ T cell responses in SIV infection

Cited by 140 publications

References 63 publications

Large TCR Diversity of Virus-Specific CD8 T Cells Provides the Mechanistic Basis for Massive TCR Renewal after Antigen Exposure

Large TCR Diversity of Virus-Specific CD8 T Cells Provides the Mechanistic Basis for Massive TCR Renewal after Antigen Exposure

Convergent recombination shapes the clonotypic landscape of the naïve T-cell repertoire

Determinants of public T cell responses

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