LAT-mediated signaling in CD4⁺CD25⁺ regulatory T cell development

Engagement of the T cell receptor for antigen (TCR) induces formation of signaling complexes mediated through the transmembrane adaptor protein, the linker for activation of T cells (LAT). LAT plays an important role in T cell development, activation, and homeostasis. A knock-in mutation at Tyr136, which is the phospholipase C (PLC)-γ1–binding site in LAT, leads to a severe autoimmune disease in mice. In this study, we show that CD4⁺CD25⁺ T reg cells that expressed Foxp3 transcription factor were nearly absent in both thymus and peripheral lymphoid organs of LAT^Y136F mice. This defect was not a result of the autoimmune environment as LAT^Y136F T reg cells also failed to develop in healthy LAT^−/− mice that received mixed wild-type and LAT^Y136F bone marrow cells. Moreover, adoptive transfer of normal CD4⁺CD25⁺ T reg cells protected neonatal LAT^Y136F mice from developing this disease. These T reg cells effectively controlled expansion of CD4⁺ T cells in LAT^Y136F mice likely via granzymes and/or TGF-β–mediated suppression. Furthermore, ectopic expression of Foxp3 conferred a suppressive function in LAT^Y136F T cells. Our data indicate that the LAT–PLC-γ1 interaction plays a critical role in Foxp3 expression and the development of CD4⁺CD25⁺ T reg cells