Subsets of Nonclonal Neighboring CD4+ T Cells Specifically Regulate the Frequency of Individual Antigen-Reactive T Cells

Laboratory of Cellular and Molecular Immunology, NIAID, NIH, Bethesda, MD 20892, USA. Electronic address: .
Immunity (Impact Factor: 21.56). 09/2012; 37(4):735-46. DOI: 10.1016/j.immuni.2012.08.008
Source: PubMed


After an immune response, the expanded population of antigen-specific CD4(+) T cells contract to steady state levels. We have found that the contraction is neither cell-autonomous nor mediated by competition for generic trophic factors, but regulated by relatively rare subsets of neighboring CD4(+) T cells not necessarily of a conventional regulatory T cell lineage. These regulators, referred to as deletors, specifically limit the frequency of particular antigen-specific T cells even though they are not reactive to the same agonist as their targets. Instead, an isolated deletor could outcompete the target for recognition of a shared, nonstimulatory endogenous peptide-MHC ligand. This mechanism was sufficient to prevent even agonist-driven autoimmune disease in a lymphopenic environment. Such a targeted regulation of homeostasis within narrow colonies of T cells with related TCR specificities for subthreshold ligands might help to prevent the loss of unrelated TCRs during multiple responses, preserving the valuable diversity of the repertoire.

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    • "Dramatic illustrations of the consequences of perturbing homeostatic processes in the peripheral immune system are found in clinical or experimentally-induced lymphopenic environments (Bosco et al., 2005;Hogan et al., 2013;Paul et al., 2013). We can reproduce the reconstitution of the repertoire by thymic output and peripheral division with the model as presented here, but the constant-death-rate assumption will need to be modified to take into account the abundance of trophic factors during recovery from lymphopenia and heterogeneity in TCR and IL-7R expression levels (Palmer et al., 2011;Singh et al., 2012). Another interesting scenario is that of post-thymic transplant dynamics in infants with DiGeorge anomaly, where thymic production is explicitly a function of time (Freitas and Rocha, 2000;Houston et al., 2011;Ciupe et al., 2009). "
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    ABSTRACT: We consider the lifetime of a T cell clonotype, the set of T cells with the same T cell receptor, from its thymic origin to its extinction in a multiclonal repertoire. Using published estimates of total cell numbers and thymic production rates, we calculate the mean number of cells per TCR clonotype, and the total number of clonotypes, in mice and humans. When there is little peripheral division, as in a mouse, the number of cells per clonotype is small and governed by the number of cells with identical TCR that exit the thymus. In humans, peripheral division is important and a clonotype may survive for decades, during which it expands to comprise many cells. We therefore devise and analyse a computational model of homeostasis of a multiclonal population. Each T cell in the model competes for self pMHC stimuli, cells of any one clonotype only recognising a small fraction of the many subsets of stimuli. A constant mean total number of cells is maintained by a balance between cell division and death, and a stable number of clonotypes by a balance between thymic production of new clonotypes and extinction of existing ones. The number of distinct clonotypes in a human body may be smaller than the total number of naive T cells by only one order of magnitude.
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    • "Interestingly, this may be enforced during thymic development of Treg cells, as the efficiency of Treg cell development for thymocytes of any given TCR is governed by readily saturable “niches” that likely relate to antigen availability (91), and this may help ensure that Treg cells specific for a wide range of self-antigens are generated in the thymus. Similarly, in the periphery competition for limited peptide–MHC niches could help ensure that the Treg cell repertoire remains sufficiently broad to maintain self-tolerance to the vast array of potential tissue-specific and systemic autoantigens (92). "
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    • "In order to explain this stability, concepts have emerged that are based on competition between T cells for limiting trophic resources needed for survival and proliferation (7). The limiting trophic resources can be divided in public and TCR-specific resources (8). In principle, public trophic resources are equally accessible to all T cells, and include stimulatory cytokines (e.g. "
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