Functional Adaptive CD4 Foxp3 T Cells Develop in MHC Class II-Deficient Mice

Abstract

CD4 Foxp3 regulatory T (TR) cells are well-defined regulator T cells known to develop in the thymus through positive selection by medium-to-high affinity TCR-MHC interactions. We asked whether Foxp3 TR cells can be generated in the complete absence of MHC class II molecules. CD4 Foxp3 TR cells are found in secondary lymphoid tissues (spleen and lymph nodes) and peripheral tissues (liver) but not the thymus of severely MHC class II-deficient (Aα−/− B6) mice. These TR cells preferentially express CD103 (but not CD25) but up-regulate CD25 surface expression to high levels in response to TCR-mediated activation. MHC class II-independent Foxp3 TR cells down modulate vaccine-induced, specific antiviral CD8 T cell responses of Aα−/− B6 mice in vivo. Furthermore, these TR cells suppress IL-2 release and proliferative responses in vitro of naive CD25− (CD4 or CD8) T cells from normal B6 mice primed by bead-coupled anti-CD3/anti-CD28 Ab as efficiently as CD4CD25high TR cells from congenic, normal B6 mice. MHC class II-independent CD4 Foxp3+ TR cells thus preferentially express the (TGF-β-induced) integrin molecule αE (CD103), are generated mainly in the periphery and efficiently mediate immunosuppressive effects.