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Abstract
T cell immunity relies on the generation and maintenance of a diverse repertoire of T cell antigen receptors (TCRs). The strength of signaling emanating from the TCR dictates the fate of T cells during development, as well as during the immune response. Whereas development of new T cells in the thymus increases the available TCR repertoire, clonal selection during the immune response narrows TCR diversity through the outgrowth of clonotypes with the fittest TCR. To ensure maintenance of TCR diversity in the antigen-selected repertoire, specific mechanisms can be envisaged that facilitate the participation of T cell clonotypes with less than best fit TCRs. Here, we summarize the evidence for the existence of such mechanisms that can prevent the loss of diversity. A number of T cell-autonomous or extrinsic factors can reverse clonotypic hierarchies set by TCR affinity for given antigen. Although not yet complete, understanding of these factors and their mechanism of action will be critical in interventional attempts to mold the antigen-selected TCR repertoire.
Highlights
Adaptive immunity provides formidable defense against an antigenically unpredictable array of infectious microbes and transformed cells
We focus on CD4+ T cells and review the current knowledge of the factors that can modify the response of distinct T cell clonotypes that would otherwise be set by T cell antigen receptors (TCRs) affinity
CD4+ T cell clonotypes with shared ability to recognize a particular antigenic peptide-MHC II (pMHCII) complex will compete for access to it, there are a number of additional factors that have been proposed to determine the outcome of clonotypic competition
Summary
Adaptive immunity provides formidable defense against an antigenically unpredictable array of infectious microbes and transformed cells. The intrinsic ability of each TCR to recognize antigenic pMHCII complexes is largely responsible for the disparate behavior of distinct CD4+ T cell clonotypes during the immune response, both in terms of expansion [10,11,12] and T helper subset differentiation [13] This disparity, in turn, underlies the enrichment of the TCR repertoire in clonotypes that display the optimum TCR signal strength under the specific conditions. Individual CD4+ T cells transferred in separate hosts exhibit substantial variance in clonal expansion, even if they express identical TCRs [9] These studies collectively support a role for TCR signal strength in clonotypic selection during both priming and memory formation, they highlight the potential influence of factors other than TCR affinity. The behavior of a given CD4+ T cell may be strongly affected by other CD4+ T cells, either through competition or regulation
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