The Repertoire of T Cells Shaped by a Single MHC/Peptide Ligand

Ignatowicz, Leszek; Kappler, John W.; Marrack, Philippa

doi:10.1016/s0092-8674(00)81028-4

Cited by 392 publications

(370 citation statements)

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“…In mice, 1-3% of preselection T cells survive thymic selection [14], and about one half to two thirds of cells that survive positive selection are eliminated during negative selection [24,[45][46][47][48][49]. We found that a thymic selection window consisting of strings at distances between 140 and 149 inclusive from the selecting pMHC roughly satisfies the constraints.…”

Section: Thymic Selection Modelmentioning

confidence: 89%

“…One would expect these T cells to have high affinity for both the foreign peptide and its presenting MHC. The consequence of having high affinity for MHC would be highly degenerate peptide binding, allowing T cells to react to self peptides [24]. Presumably, such cells would normally be eliminated in vivo by negative selection because of their high affinity for MHC, not because of high affinity for a self peptide.…”

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confidence: 99%

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The effects of thymic selection on the range of T cell cross‐reactivity

Chao¹,

Davenport²,

Forrest³

et al. 2005

Eur J Immunol

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Based on the results of a computational model of thymic selection, we propose a mechanism that produces the observed wide range of T cell cross-reactivity. The model suggests that the cross-reactivity of a T cell that survives thymic selection is correlated with its affinity for self peptides. In order to survive thymic selection, a T cell with low affinity for all self peptides expressed in the thymus must have high affinity for major histocompatibility complex (MHC), which makes it highly cross-reactive. A T cell with high affinity for any self peptide must have low MHC affinity to survive selection, which makes it highly specific for its cognate peptide. Our model predicts that (1) positive selection reduces by only 17% the number of T cells that can detect any given foreign peptide, even though it eliminates over 95% of pre-selection cells; (2) negative selection decreases the average cross-reactivity of the pre-selection repertoire by fivefold; and (3) T cells responding to foreign peptides similar to self peptides will have a lower average cross-reactivity than cells responding to epitopes dissimilar to self. IntroductionThe ability of an individual T cell to recognize related antigenic peptides is an essential part of the body's defense against mutating pathogens. T cells detect intracellular pathogens by binding to foreign peptides presented by major histocompatibility complex (MHC)-encoded proteins on the surfaces of infected cells or on specialized antigen-presenting cells [1][2][3]. Although T cells are specific to their cognate peptides, they crossreact with many others [4]. It has been estimated that a T cell can detect an average of 10 6 different peptides [5]. However, not all T cells are equally cross-reactive; it has been observed that the number of peptides to which a single T cell can respond varies widely [6].T cell recognition of antigen is determined by binding interactions of T cell receptors (TCR) with peptide-MHC complexes (pMHC). Each T cell expresses thousands of copies of identical TCR that bind with high affinity to their cognate peptide presented by MHC. T cells detect the presence of pathogens when their receptors have sufficiently high affinity for the pMHC on a target cell and remain in contact with pMHC for a time sufficient to generate a stimulatory signal. Because the pMHC presents a single binding target for the TCR [7], both the peptide and the structure of the presenting MHC molecule play a role in determining affinity.TCR are initially generated by V(D)J recombination, with specificities to a wide range of peptides, including self peptides generated from normal proteins produced by healthy cells [8,9]. Most self-reactive T cells are screened out early in their maturation process in the thymus, where they are exposed to a large array of the body's peptides presented on MHC molecules [10]. During positive selection, T cells that have an extremely low avidity to self peptides bound to MHC die by neglect [11][12][13]. It is believed that this process eliminates T cells that ha...

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Section: Thymic Selection Modelmentioning

confidence: 89%

mentioning

confidence: 99%

The effects of thymic selection on the range of T cell cross‐reactivity

Chao¹,

Davenport²,

Forrest³

et al. 2005

Eur J Immunol

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“…The extent of CD8 + T cell cross-reactivity remains controversial with evidence both for [10][11][12][13][14][15][16][17] and against [18][19][20][21][22] its broad effectiveness. At least in the one animal tested on two occasions, we observed cross-reactivity of CD8 + T cells with 50% of tested epitope variants not present in the vaccine (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…A number of studies have addressed this point with mixed results. While some studies clearly detected cross-clade-reactive HIV-1-specific CD8 + T cell responses [10][11][12][13][14][15][16][17], there is substantial evidence that CD8 + T cells can be highly sequence-specific [18][19][20][21][22]. This was best demonstrated in systematic studies employing all possible single amino acid substitutions in each position of an MHC class I epitope, which suggested that as few as one in three epitope variants was recognized by a given T cell receptor [18,23].…”

Section: Introductionmentioning

confidence: 99%

Induction of long‐lasting multi‐specific CD8⁺T cells by a four‐component DNA‐MVA/HIVA‐RENTA candidate HIV‐1 vaccine in rhesus macaques

Nkolola

Gléria

et al. 2006

Eur J Immunol

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As a part of a long‐term effort to develop vaccine against HIV‐1 clade A inducing protective T cell responses in humans, we run mutually complementing studies in humans and non‐human primates (NHP) with the aim to maximize vaccine immunogenicity. The candidate vaccine under development has four components, pTHr.HIVA and pTH.RENTA DNA, and modified vaccinia virus Ankara (MVA).HIVA and MVA.RENTA, delivered in a heterologous DNA prime‐MVA boost regimen. While the HIVA (Gag/epitopes) components have been tested in NHP and over 300 human subjects, we plan to test in humans the RENTA (reverse transcriptase, gp41, Nef, Tat) vaccines designed to broaden HIVA‐induced responses in year 2007. Here, we investigated the four‐component vaccine long‐term immunogenicity in Mamu‐A*01‐positive rhesus macaques and demonstrated that the vaccine‐induced T cells were multi‐specific, multi‐functional, readily proliferated to recall peptides and were circulating in the peripheral blood of vaccine recipients over 1 year after vaccine administration. The consensus clade A‐elicited T cells recognized 50% of tested epitope variants from other HIV‐1 clades. Thus, the DNA‐MVA/HIVA‐RENTA vaccine induced memory T cells of desirable characteristics and similarities to those induced in humans by HIVA vaccines alone; however, single‐clade vaccines may not elicit sufficiently cross‐reactive responses.

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“…Surprisingly, these CD4 1 T cells expresses a wide variety of different Vb segments in their TCRs, indicating that relatively diverse T-cell repertoire can develop in the presence of a single peptide/MHC class II ligand. 27 Furthermore, these CD4 1 T cells reacted with the same MHC class II molecule bound to other antigenic peptides, including one that was quite different from the selecting peptide in TCR-binding residues. 28 Thus, the TCR crossreactivity is not an unusual phenomenon and may represent an important aspect of TCR recognition in the thymus as well as in the periphery.…”

Section: Specificity and Plasticity Of Tcrsmentioning

confidence: 98%

Cross-immune tolerance: conception and its potential significance on transplantation tolerance

Zhao

2009

Cell Mol Immunol

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The Repertoire of T Cells Shaped by a Single MHC/Peptide Ligand

Cited by 392 publications

References 54 publications

The effects of thymic selection on the range of T cell cross‐reactivity

The effects of thymic selection on the range of T cell cross‐reactivity

Induction of long‐lasting multi‐specific CD8⁺T cells by a four‐component DNA‐MVA/HIVA‐RENTA candidate HIV‐1 vaccine in rhesus macaques

Cross-immune tolerance: conception and its potential significance on transplantation tolerance

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The Repertoire of T Cells Shaped by a Single MHC/Peptide Ligand

Cited by 392 publications

References 54 publications

The effects of thymic selection on the range of T cell cross‐reactivity

The effects of thymic selection on the range of T cell cross‐reactivity

Induction of long‐lasting multi‐specific CD8+ T cells by a four‐component DNA‐MVA/HIVA‐RENTA candidate HIV‐1 vaccine in rhesus macaques

Cross-immune tolerance: conception and its potential significance on transplantation tolerance

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Induction of long‐lasting multi‐specific CD8⁺T cells by a four‐component DNA‐MVA/HIVA‐RENTA candidate HIV‐1 vaccine in rhesus macaques