Microbiota-Specific Foxp3+ Regulatory T Cells Could Control Pathological T Helper Responses

Upon engaging cognate peptide MHC-II complexes (pMHC-IIs), naive CD4+ T cells differentiate and acquire several T helper (Th) fates, guided by a dynamic cytokine milieu following antigenic challenge. This physiological Th fate choice process is often erroneously conflated with a maladaptive pathological process historically termed Th polarization. Here we propose why these two processes are distinct and separable. We posit that, though innate signaling alone is sufficient for Th fate choice in naive CD4+ T cells, Th polarization instead strictly originates from pre-existing cross-reactive memory CD4+ T cells. We further posit that Th polarization is normally prevented by thymus-derived cross-reactive antigen-specific regulatory T cells (Tregs) and inevitably manifests as immunopathology when the Treg repertoire and the microbiota that maintains it are selectively depleted. Bifurcating Th fate choice and polarization delineate Th effector pathways more accurately and tangibly improve the scope of targeted therapies for allergies, autoimmune diseases, and effective vaccines.