Congenital T cell activation impairs transitional to follicular B cell maturation in humans

CTLA4-deficient patients exhibit profound humoral immune dysfunction, yet the basis for the B cell defect is not known. We observed a marked reduction in transitional to follicular B cell development in CTLA4-deficient patients, correlating with decreased CTLA4 function in regulatory T cells and increased mTORC1 signaling in transitional B cells. Treatment of transitional B cells with CD40L was sufficient to induce mTORC1 signaling and inhibit follicular B cell maturation in vitro . Frequent cell-cell contacts between CD40L + T cells and naïve IgD + CD27 − B cells were observed in patient lymph nodes. Follicular B cell maturation in CTLA-deficient patients was partially rescued following CTLA4 replacement therapy in vivo . We conclude that functional regulatory T cells and the containment of excessive T cell activation are required for follicular B cells to mature and attain metabolic quiescence and thus acquire a state of immunological self-tolerance. One Sentence Summary Congenital T cell activation in CTLA4-deficient patients impairs transitional to follicular B cell maturation and can be rescued by CTLA4 replacement therapy in vivo .