Blockade of B7-H1 (Programmed Death Ligand 1) Enhances Humoral Immunity by Positively Regulating the Generation of T Follicular Helper Cells

Abstract

T follicular helper (TFH) cells are critical initiators in the development of T cell-dependent humoral immunity and the generation of protective immunity. We demonstrate that TFH cell accumulation and Ab production are negatively regulated by B7-H1 (programmed death ligand 1) in response to both helminth infection and active immunization. Following immunization of B7-H1?/? mice with keyhole limpet hemocyanin or helminth Ags, there is a profound increase in induction of TFH cells as a result of increased cell cycling and decreased apoptosis relative to wild-type mice. The increase in TFH cells in the absence of B7-H1 was associated with significant elevations in Ag-specific Ig response. Cotransfer experiments in vivo demonstrated that B7-H1 expression on B cells was required for negatively regulating TFH cell expansion and production of Ag-specific Ig. Treatment of immunized wild-type mice with anti?B7-H1 or anti-programmed death 1 mAbs, but not anti?B7-DC, led to a significant expansion of the TFH cell population and an enhanced Ag-specific Ig response. Our results demonstrate that the coinhibitory B7-H1/programmed death 1 pathway can limit the expansion of TFH cells and constrain Ag-specific Ig responses. This finding has direct implications for investigations examining the feasibility of therapeutically manipulating this pathway and reveals new insights into the regulation of the humoral immune response.