Tissue-specific emergence of regulatory and intraepithelial T cells from a clonal T cell precursor.

Peripheral Foxp3+ regulatory T cells (pTregs) maintain immune homeostasis by controlling potentially harmful effector T cell responses toward dietary and microbial antigens. Although the identity of the T cell receptor (TCR) can impose commitment and functional specialization of T cells, less is known about how TCR identity governs pTreg development from conventional CD4+ T cells. To investigate the extent to which TCR identity dictates pTreg fate, we used somatic cell nuclear transfer to generate a transnuclear (TN) mouse carrying a monoclonal TCR from a pTreg (pTreg TN mice). We found that the pTreg TCR did not inevitably predispose T cells to become pTreg but instead allowed for differentiation of noninflammatory CD4+CD8αα+ intraepithelial lymphocytes (CD4IELs) in the small intestine. Only when we limited the number of T cell precursors that carried the TN pTreg TCR did we observe substantial pTreg development in the mesenteric lymph nodes and small intestine lamina propria of mixed bone marrow chimeras. Small clonal sizes and therefore decreased intraclonal competition were required for pTreg development. Despite bearing the same TCR, small intestine CD4IEL developed independently of precursor frequency. Both pTreg and CD4IEL development strictly depended on the resident microbiota. A single clonal CD4+ T cell precursor can thus give rise to two functionally distinct and anatomically segregated T cell subsets in a microbiota-dependent manner. Therefore, plasticity of the CD4 T cell compartment depends not only on the microbiota but also on specialized environmental cues provided by different tissues.