Abstract
BACKGROUND: LPS-responsive beige-like anchor protein (LRBA) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) deficiencies give rise to overlapping phenotypes of immune dysregulation and autoimmunity, with dramatically increased frequencies of circulating follicular helper T (cT(FH)) cells. OBJECTIVE: We sought to determine the mechanisms of cT(FH) cell dysregulation in patients with LRBA deficiency and the utility of monitoring cT(FH) cells as a correlate of clinical response to CTLA4-Ig therapy. METHODS: cT(FH) cells and other lymphocyte subpopulations were characterized. Functional analyses included in vitro follicular helper T (T(FH)) cell differentiation and cT(FH)/naive B-cell cocultures. Serum soluble IL-2 receptor α chain levels and in vitro immunoglobulin production by cultured B cells were quantified by using ELISA. RESULTS: cT(FH) cell frequencies in patients with LRBA or CTLA4 deficiency sharply decreased with CTLA4-Ig therapy in parallel with other markers of immune dysregulation, including soluble IL-2 receptor α chain, CD45RO(+)CD4(+) effector T cells, and autoantibodies, and this was predictive of favorable clinical responses. cT(FH) cells in patients with LRBA deficiency were biased toward a T(H)1-like cell phenotype, which was partially reversed by CTLA4-Ig therapy. LRBA-sufficient but not LRBA-deficient regulatory T cells suppressed in vitro T(FH) cell differentiation in a CTLA4-dependent manner. LRBA-deficient T(FH) cells supported in vitro antibody production by naive LRBA-sufficient B cells. CONCLUSIONS: cT(FH) cell dysregulation in patients with LRBA deficiency reflects impaired control of T(FH) cell differentiation because of profoundly decreased CTLA4 expression on regulatory T cells and probably contributes to autoimmunity in patients with this disease. Serial monitoring of cT(FH) cell frequencies is highly useful in gauging the clinical response of LRBA-deficient patients to CTLA4-Ig therapy.