Differentiation of human thymic regulatory T cells at the double positive stage

Treg cells, best identified by the expression of the transcription factor FOXP3, play a crucial role in maintaining self‐tolerance. Natural Treg cells constitute an independent thymus‐derived T‐cell lineage whose developmental program in humans is still ill‐defined. Here, we provide evidence of a Treg‐cell differentiation pathway at the double positive (DP) stage, prior to commitment to the CD4+ or CD8+ lineage, in pediatric thymuses. FOXP3+ DP cells displayed a functional IL‐7 receptor and increased Bcl‐2 levels that may protect them from cell death/negative selection, and an activated/suppressive phenotype that was lost as CD4 single positive (SP) cells matured and acquired egress markers. A subpopulation of FOXP3+ DP thymocytes expressing CD103 likely represents the precursor of FOXP3+ CD8SP cells, which homogeneously expressed this mucosal‐homing molecule. Finally, co‐cultures of DP thymocytes with primary thymic epithelial cells and multiple linear regression analyses support that FOXP3+ SP cells are largely derived from FOXP3+ DP thymocytes. Overall, our data suggest that human Treg‐cell lineage commitment significantly occurs at the DP stage with possible implications for the diversity and autoreactivity of the natural Treg‐cell repertoire.

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