A 33D1+ Dendritic Cell/Autoreactive CD4+ T Cell Circuit Maintains IL-2–Dependent Regulatory T Cells in the Spleen

Phenotypically and functionally diverse regulatory T (Tr) cell subsets populate lymphoid and nonlymphoid tissues, where their maintenance and function are governed by unique homeostatic signals. Whereas Tr cells resident in nonlymphoid tissues depend on continual TCR signaling for their survival and function, phenotypically naive Tr cells occupying secondary lymphoid organs are largely supported by paracrine IL-2 signaling. Crucially, the absence of either of these distinct Tr cell subsets results in pathogenic autoimmunity, underscoring their nonredundant roles in the preservation of self-tolerance. However, the cellular and molecular factors precipitating IL-2 release and subsequent maintenance of secondary lymphoid organ-resident Tr cells are still poorly understood. In this study, we report that IL-2-dependent Tr cells in the spleen compete for a limiting supply of paracrine IL-2 generated by autoreactive CD4(+) T cells in response to MHC class II-restricted autoantigen activation by 33D1(+)CD11b(int) dendritic cells. Manipulating this cellular circuit culminating in IL-2 production could have clinical benefits in settings in which diminished Tr cell abundance is desired.