Clonal Bifurcation of Foxp3 Expression Visualized in Thymocytes and T Cells.

Regulatory T cells (Tregs) are crucial for suppressing autoimmunity and inflammation mediated by conventional T cells. To be useful, some Tregs should have overlapping specificity with relevant self-reactive or pathogen-specific clones. Whether matching recognition between Tregs and non-Tregs might arise through stochastic or deterministic mechanisms has not been addressed. We tested the hypothesis that some Tregs that arise in the thymus or that are induced during Ag-driven expansion of conventional CD4 T cells might be clonally related to non-Tregs by virtue of asymmetric Foxp3 induction during cell division. We isolated mouse CD4 thymocytes dividing in vivo, wherein sibling cells exhibited discordant expression of Foxp3 and CD25. Under in vitro conditions that stimulate induced Tregs from conventional mouse CD4 T cells, we found a requirement for cell cycle progression to achieve Foxp3 induction. Moreover, a substantial fraction of sibling cell pairs arising from induced Treg stimulation also contained discordant expression of Foxp3. Division-linked yet asymmetric induction of Treg fate offers potential mechanisms to anticipate peripheral self-reactivity during thymic selection as well as produce precise, de novo counterregulation during CD4 T cell-mediated immune responses.