Role of self-peptides in positively selecting the T-cell repertoire

Nikolić‐Žugić, Janko; Bevan, Michael J.

doi:10.1038/344065a0

Cited by 269 publications

(145 citation statements)

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“…There are data that have been differentially interpreted to show that positive selection is either peptide specific (Ashton-Rickardt, 1993;Ashton-Rickardt and Tonegawa, 1994;AshtonRickardt et al, 1993;Goldrath and Bevan, 1999;Hogquist et al, 1994;Hsu et al, 1995;Nakano et al, 1997;Nikolic-Zugic and Bevan, 1990) or peptide-unspecific (Bachmann et al, 1993;Barnden et al, 1994;Berg et al, 1999;Ernst et al, 1999;Ignatowicz et al, 1996;Kisielow et al, 1988;Lee et al, 1999;Schumacher and Ploegh, 1994;Von Boehmer, 1994). The ambiguity of interpretation arises because peptide plays a role in the stability of R, in the expression of the allele-specific determinant, as well as in the specific signaling interaction with anti-P.…”

Section: Is Positive Selection [P+anti-p]-independent (Ie Peptide-mentioning

confidence: 99%

The Tritope Model for restrictive recognition of antigen by T-cells

Cohn

2008

Molecular Immunology

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Based on the Tritope model of the TCR (Cohn, 2005c), a set of functional and evolutionary problems surrounding restrictive recognition of antigen are discussed. These include the origin of allelespecific recognition, the selection pressures for polygeneism and polymorphism, the TCR signaling interactions, the centrality of effector T-helper (eTh)-dependence for activation, the role of haplotype exclusion, "nonclassical" MHC-elements, alloreactivity versus xenoreactivity, etc. Further, a set of observations believed to support the Standard Model are reinterpreted.A previous paper (Cohn, 2005c) detailed a new model (referred to as the Tritope Model) of the T-cell antigen-receptor (TCR) and analyzed its effectiveness in dealing with three basic phenomena, restrictive recognition, positive selection and allorecognition. The reasons for developing a model competing with the Standard Model have been discussed (Cohn, 2003;Cohn, 2004a;Cohn, 2004b;Cohn, 2006a;Langman and Cohn, 1999). Here we will extend the analysis of the Tritope Model by considering a set of phenomena related to the genetics, ontogeny and evolution of the TCR-MHC system. Further, the steps in the Self (S)-Nonself (NS) discrimination that are affected by the Tritope Model will be analyzed. Recalling the Tritope Model (Cohn, 2005c)The TCR encodes two distinctly different repertoires. One is germline-selected to recognize the allele-specific determinants (a) on the MHC-encoded restricting elements (R) of the species; the other is a somatically generated random repertoire that recognizes peptide (P) bound to the restricting element (R) as [PR].In order to map the two repertoires onto the TCR structure it was argued that (see List of Abbreviations):1. Single V-gene segments, Vα or Vβ, encode recognition of the allele-specific determinants (a). 2.Each domain (RI) or subunit (RII) of the R-element expresses an allele-specific determinant (a) (i.e., 2a per R).3. Peptide (P) is recognized by an anti-P site on the TCR formed by complementation of the CDR3 junctional regions of the α and β subunits.

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Section: Is Positive Selection [P+anti-p]-independent (Ie Peptide-mentioning

confidence: 99%

The Tritope Model for restrictive recognition of antigen by T-cells

Cohn

2008

Molecular Immunology

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“…bm8 mice are unable to mount an H-2K-restricted immune response to OVA. This has been shown to be due to absence of positive selection of OVA-specific T cells (27). In fact, an OVA-specific, K b -restricted TCR transgene (OT-I) is also not selected in bm8 mice (28).…”

Section: Positive Selection Is Limited By Available Peptide-dependentmentioning

confidence: 99%

“…Despite the fact that the endogenously processed OVA 257-264 SIINFEKL (OVAp) binds K bm8 , it is unable to stimulate OVAspecific CTL in the context of K bm8 (27,32). Before searching for peptides that would restore positive selection of OVA-specific receptors, we sought to determine whether peptides could be targets for OVA-specific CTL in the context of K bm8 , and how frequent they are.…”

Section: Peptides That Can Be Recognized By Ova-specific Ctl In the Cmentioning

confidence: 99%

Positive Selection Is Limited by Available Peptide-Dependent MHC Conformations

Stefanski

Jameson

Hogquist

2000

The Journal of Immunology

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Recent data suggest that the diversity of self peptides presented in the thymus during development contributes to positive selection of a diverse T cell repertoire. We sought to determine whether a previously defined “hole in the immunological repertoire” could be explained by the absence of an appropriate selecting self peptide. The repertoire defect in question is the inability of bm8 mice to make an H-2K-restricted response to OVA. Like other OVA-specific, H-2K-restricted receptors, OT-I-transgenic T cells are not positively selected in bm8 mice. Using criteria we had previously established for identifying positive selection ligands, we found peptides that could restore positive selection of OT-I thymocytes in bm8 mice. Thus, the T cell repertoire can be limited by a requirement for specific self peptides during development. Data with MHC-specific Abs suggested that peptides might be able to force MHC residues to adopt different conformations in Kb vs Kbm8. This shows that peptides can potentially contribute to ligand diversity both directly (via variability in the solvent-exposed side chains) and indirectly (through their effect on the MHC conformation). Our data support a model where self peptide diversity allows selection of T cells specific for a broad range of MHC conformations.

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“…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 have such poor avidity to MHC that they would not bind to any pMHC.…”

Section: Introductionmentioning

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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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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Role of self-peptides in positively selecting the T-cell repertoire

Cited by 269 publications

References 0 publications

The Tritope Model for restrictive recognition of antigen by T-cells

The Tritope Model for restrictive recognition of antigen by T-cells

Positive Selection Is Limited by Available Peptide-Dependent MHC Conformations

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

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