On the Plausibility of the Clonal Expansion Theory of the Immune System in Terms of the Combinatorial Possibilities of Amino-acids in Antigen and Self-tolerance

Whitaker, Laura; Renton, Adrian

doi:10.1006/jtbi.1993.1171

Cited by 13 publications

(9 citation statements)

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“…Rescuing thymocytes with anti-CD3 (23), or anti-TCR␣␤ (24) Abs instead of MHC molecule with a covalently bound peptide, gives similar estimates. Finally, theoretical models based on the assumption that evolution minimizes the size of the preselection repertoire, suggest f N Ϸ 37% (27)(28)(29)(30). Our analysis supports these latter estimates by showing that a repertoire in which more than 1% of the clones are alloreactive can be obtained only if a large fraction of the cells is deleted by negative selection.…”

Section: Discussionsupporting

confidence: 72%

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Deriving Quantitative Constraints on T Cell Selection from Data on the Mature T Cell Repertoire

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Perelson³

2000

The Journal of Immunology

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The T cell repertoire is shaped in the thymus through positive and negative selection. Thus, data about the mature repertoire may be used to infer information on how TCR generation and selection operate. Assuming that T cell selection is affinity driven, we derive the quantitative constraints that the parameters driving these processes must fulfill to account for the experimentally observed levels of alloreactivity, self MHC restriction and the frequency of cells recognizing a given foreign Ag. We find that affinity-driven selection is compatible with experimental estimates of these latter quantities only if 1) TCRs see more peptide residues than MHC polymorphic residues, 2) the majority of positively selected clones are deleted by negative selection, 3) between 1 and 3.6 clonal divisions occur on average in the thymus after completion of TCR rearrangement, and 4) selection is driven by 103–105 self peptides.

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Section: Discussionsupporting

confidence: 72%

“…27), and f N is the fraction of positively selected clones that survive negative selection (27)(28)(29)(30). The values of f and f N can be inferred from recent experimental data (see below).…”

Section: Positive and Negative Selectionmentioning

confidence: 99%

Deriving Quantitative Constraints on T Cell Selection from Data on the Mature T Cell Repertoire

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Perelson³

2000

The Journal of Immunology

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“…De Boer and Perelson 27 and Whitaker and Renton 28 have arrived at similar conclusions based on somewhat different assumptions and parameters. Unlike the theories of these authors, the present model does not impose the assumption that S is small relative to A, and it takes into account the likely possibility that much more than minimal 'coverage' may be required for immunological protection (see text and Box 2 for details.…”

Section: Box I Is There An Optimal Level Of Antigen Receptor Degeneracy?mentioning

confidence: 81%

Antigen receptor ‘capacity’ and the sensitivity of self-tolerance

Nemazee

1996

Immunology Today

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“…Interestingly, probabilistic models of clonal deletion based on the hypothesis that evolution optimizes the size of the repertoire predicted f N = 0 37 (57)(58)(59). This estimate will be used here.…”

Section: Modelmentioning

confidence: 99%

Explaining high alloreactivity as a quantitative consequence of affinity-driven thymocyte selection

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Perelson

1999

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

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Interactions between T cell receptors and peptides bound to molecules encoded by the MHC genes underly T cell activation. More than 1% of T cells are activated by foreign (allogenic) MHC molecules, a phenomenon called alloreactivity. Reconciling the high frequency of alloreactivity with the fact that only 1 T cell in 10 4 -10 6 responds to a given foreign antigen presented on self MHC has been a longstanding puzzle. We show, by using a quantitative model, that this difference follows from the affinity model of T cell selection. Further, we demonstrate that highly alloreactive pre-and post-selection repertoires can be obtained without assuming germline bias of T cell receptors toward recognition of allelespecific MHC residues. It has been proposed that alloreactivity occurs because self and foreign MHCs bind different subsets of self peptides or alter their conformation differently. We find that such effects decrease rather than increase alloreactivity. Overall, our results show that the affinity model of T cell selection can quantitatively explain both self MHC restriction and high alloreactivity.Maturation of T cells in the thymus involves a two-step selection process driven by the affinity of their T cell receptors (TCR) for self peptides presented on proteins encoded by MHC genes. The first step, positive selection (1, 2), disgards thymocytes bearing TCRs with low affinity for MHC-peptide complexes expressed in the thymus. This eliminates T cells that cannot recognize MHC molecules. The second step, negative selection (3, 4), deletes cells with high affinity receptors for thymic MHC-peptide complexes. Thus, removing many self reactive cells. Overall, only 3% of the T cells produced in the thymus have TCRs with the intermediate affinity required to reach the periphery (5).Because MHC genes are extremely polymorphic, two individuals are very unlikely to express the same set of MHC molecules. As a result of positive selection, T cells are self MHC restricted: they recognize pathogens presented by self MHC molecules but ignore them if presented by foreign MHC molecules (6-14). MHC polymorphism is also the main obstacle to tissue transplantation (15). Typically, 1-24% of T cells are alloreactive (16, 17), i.e., they respond to foreign (allogenic) MHC molecules. Reconciling this high alloresponse frequency with the fact that among naive T cells only 1 in 10 4 -10 6 recognizes a given pathogen (18, 19) is a long-standing immunological puzzle. In this paper, we examine quantitatively three hypotheses proposed to explain the high frequency of alloreactivity.The first hypothesis, due to Matzinger and Bevan (20), suggests that the 2-4 orders of magnitude difference between antigen and MHC response frequencies results from the difference in the diversity of these two types of molecule on the surface of antigen presenting cells (APCs). Because each individual expresses only a few distinct MHC molecules and eachThe publication costs of this article were defrayed in part by page charge payment. This article must the...

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On the Plausibility of the Clonal Expansion Theory of the Immune System in Terms of the Combinatorial Possibilities of Amino-acids in Antigen and Self-tolerance

Cited by 13 publications

References 0 publications

Deriving Quantitative Constraints on T Cell Selection from Data on the Mature T Cell Repertoire

Deriving Quantitative Constraints on T Cell Selection from Data on the Mature T Cell Repertoire

Antigen receptor ‘capacity’ and the sensitivity of self-tolerance

Explaining high alloreactivity as a quantitative consequence of affinity-driven thymocyte selection

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