Abstract
Conventional and regulatory T cells develop in the thymus where they are exposed to samples of self-peptide MHC (pMHC) ligands. This probabilistic process selects for cells within a range of responsiveness that allows the detection of foreign antigen without excessive responses to self. Regulatory T cells are thought to lie at the higher end of the spectrum of acceptable self-reactivity and play a crucial role in the control of autoimmunity and tolerance to innocuous antigens. While many studies have elucidated key elements influencing lineage commitment, we still lack a full understanding of how thymocytes integrate signals obtained by sampling self-peptides to make fate decisions. To address this problem, we apply stochastic models of signal integration by T cells to data from a study quantifying the development of the two lineages using controllable levels of agonist peptide in the thymus. We find two models are able to explain the observations; one in which T cells continually re-assess fate decisions on the basis of multiple summed proximal signals from TCR-pMHC interactions; and another in which TCR sensitivity is modulated over time, such that contact with the same pMHC ligand may lead to divergent outcomes at different stages of development. Neither model requires that T and T are differentially susceptible to deletion or that the two lineages need qualitatively different signals for development, as have been proposed. We find additional support for the variable-sensitivity model, which is able to explain apparently paradoxical observations regarding the effect of partial and strong agonists on T and T development.
Highlights
Conventional CD4z T cells (Tconv) and CD4z T regulatory cells (Treg) are essential components of the adaptive immune system
Without T cell receptor (TCR) sensitivity varying during development, a model in which fate decisions derive from single TCRpMHC contacts is unable to explain the data
Assuming there is a positive relationship between TIM peptide presentation (t) and relative TIM RNA expression, equation 4 shows that a model in which fate decisions are re-evaluated after single TCR-peptide-major histocompatibility complex (MHC) ligands (pMHC) contacts (p~1) can describe the Tconv data, which falls progressively with t
Summary
Conventional CD4z T cells (Tconv) and CD4z T regulatory cells (Treg) are essential components of the adaptive immune system. Conventional T cells develop effector function in response to foreign antigens, while natural T regulatory cells produced in the thymus play a key role in the maintenance of tolerance to selfantigens and prevent autoimmune diseases (reviewed in, for example, [1]). Both populations are derived from precursors in the thymus that develop, undergo selection and differentiate into different T cell lineages. The differentiation of a thymocyte into the mature ab T cell repertoire is dependent on the engagement of its T cell receptor (TCR) with endogenous peptides presented by major histocompatibility complex (MHC) molecules on thymic antigen presenting cells. The precise rules underlying T cell precursor fate are not well understood; based on its exposure to a sample of pMHC, how and when does a thymocyte decide to become a Tconv, a Treg, or be deleted?
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