The thymus-derived Foxp3+ regulatory T cells (Tregs) represent a unique population of CD4+ T cells responsible for maintaining dominant tolerance to auto-antigens, beneficial microbiota and potential irritants such as allergens on the one hand and efficient but balanced defense against pathogens on the other. How Tregs with high-affinity TCRs for thymically expressed epitopes survive thymic deletion or display such broad functionality is presently unclear. We recently introduced a novel framework dubbed SPIRAL (SPecific ImmunoRegulatory ALgorithm) which suggests that antigen cross-reactivity of thymic Treg repertoire could provide a mechanistic basis for its broad functionality. Here we further develop this model to propose how escape of high-affinity Tregs from thymic purge could be achieved in dyads with high-affinity natural IL-2-producing T cells (IL-2p T cells) sharing TCR epitope cross-reactivity. We believe this interpretation could reconcile contradictions related to Treg ontogeny in the thymus and their role in modulating antigen-specific immune responses.
The 'Hygiene hypothesis', a cornerstone model to account for the role of exogenous pathogens and later of endogenous microbiota in immune disorders, is currently presumed to operate at the innate immunity and metabolite levels to properly 'educate' the immune system. Doing so however fails to satisfactorily account for the antigen-specific nature of such disorders.SPIRAL is a novel interpretive framework that resolves this dilemma. It represents the periodic
Naive CD4+ T cells engage cognate peptide MHC-II complexes (pMHC-IIs) to differentiate and acquire one of several T helper (Th) fates whose specific trajectories are guided by a dynamic cytokine milieu that develops in response to antigenic entity. This physiological process is often erroneously conflated with a pathological one termed Th polarization. Using the SPIRAL model, we argue here that unlike Th fate choice, innate signaling alone is insufficient to initiate Th polarization in naive CD4+ T cells, that it instead develops from pre-existing memory CD4+ T cells that express cross-reactive TCRs, and that it inevitably leads to immunopathology.
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