A very high level of crossreactivity is an essential feature of the T-cell receptor

Mason, Don

doi:10.1016/s0167-5699(98)01299-7

Cited by 870 publications

(736 citation statements)

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“…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].…”

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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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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“…Furthermore, microchimerisms may also result from transplantation or blood transfusion, or occur from in utero transfer between twins [12]. Given that a low level of autoreactivity is even found in healthy individuals [17], and it is well documented that antigen recognition by B lymphocytes [18] and T lymphocytes [19] is promiscuous, it may be assumed that lymphocyte clones stimulated by an alloantigen may also react with a similar host allele.…”

Section: Introductionmentioning

confidence: 99%

Single nucleotide polymorphisms as a prerequisite for autoantigens

et al. 2005

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It is still elusive why certain self proteins induce an autoimmune response. One immunological hypothesis is that only modified or altered self‐proteins may become a target. Thus, we asked whether such alterations may actually be genetic polymorphisms that can be revealed by analyzing sequence variability in the known human autoantigens. Indeed, we found autoantigens to contain significantly more single nucleotide polymorphisms (SNP) than other human genes do. Our finding may offer an explanation for autoimmune responses through allogeneic exposure. Besides other contributing factors in autoimmunity, SNP may represent an essential prerequisite for the primary induction of an autoimmune response.See accompanying Commentary: http://dx.doi.org/10.1002/eji.200425888

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“…Indeed, there is mounting evidence that a given TCR often displays a considerable degree of crossreactivity in their recognition of antigenic peptide/MHC complexes. 7,8,[21][22][23] In some cases, the different antigenic peptides recognized by a given clonotypic TCR do not share obvious sequence homology. 24,25 Furthermore, such TCR crossreactivity involves not only the recognition of different antigenic peptides bound to the same MHC molecule, but also the recognition of antigenic peptides bound to other MHC molecules.…”

Section: Specificity and Plasticity Of Tcrsmentioning

confidence: 99%

“…8 As viewed from a high vintage point, such TCR crossreactivity may be developmentally programmed in the thymus. Positive selection in the thymus is well known to be self-antigendependent and requires weaker TCR signals.…”

Section: Specificity and Plasticity Of Tcrsmentioning

confidence: 99%

“…In fact, such TCR flexibility is not unique to transplant models and may represent a general feature of Tcell recognition of a wide variety of antigenic epitopes. 7,8 The high responder frequency of alloreactive T cells in the T-cell repertoire, the presence of extensive crossreactivity to other nominal antigens and the involvement of memory T cells make the induction of transplantation tolerance a challenging task. 9,10 To accomplish this task, all the T cells that are potentially reactive to transplant antigens need to be tolerized by means of deletion, anergy or regulatory T (Treg)-cell-mediated active suppression.…”

Section: Introductionmentioning

confidence: 99%

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