https://orcid.org/0000-0001-7850-2658
Key Points
Congenital T cell activation in CTLA4-deficient patients impairs transitional to follicular B cell maturation.
Follicular B cell maturation can be rescued in CTLA4 deficiency by CTLA4 replacement therapy in vivo.
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, increased CD40L levels in effector CD4+ 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 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 may be required for human transitional B cells to mature and attain metabolic quiescence at the follicular B cell stage.
