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

Abstract 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. Competing Interest Statement JRF was supported by an investigator-initiated research grant from Bristol Myers Squibb. AKS is a founder and on the scientific advisory board of Honeycomb Biotechnologies, which is developing Seq-Well arrays for commercial use. SP is on the SAB of Abpro Inc, Paratus and BE Biopharma Inc. All other authors declare that they have no competing interests.