PD-L1 plays a B cell-intrinsic role in suppressing the antibody response and anti-tumor immunity.

Abstract

Abstract The discovery that PD-L1 inhibits PD-1 on CD8+ T cells has led to new mechanistic insights into the regulation of host immune responses. The contribution of PD-L1 expressed by different immune cell types remains poorly understood, partly due to the lack of cell type-specific Cd274 (encoding PD-L1) knockout mice. Here, to address the role of B cell-expressed PD-L1 in antibody response and tumor development, we have generated AicdacreCd274fl/fl mice, in which PD-L1 was ablated only in activated B cells. As compared to their wild-type littermates, AicdacreCd274fl/fl mice showed normal development and maintenance of B cells, T cells, DCs and macrophages, while mounting a stronger T-dependent high affinity NP-binding IgM, IgG1 and IgG2a titers upon immunization with NP-CGG plus alum. Such phenotype was copied by C57 mice treated with a blocking αPD-L1 antibody. Tumor growth from engrafted E0771 breast cancer cells in AicdacreCd274fl/fl mice was significantly delayed, in association with increased CD8+ T cell infiltration and activities. Moreover, B cells isolated from AicdacreCd274fl/fl mice or those treated with aPD-L1 displayed higher levels of proliferation and differentiation to plasma cells upon in vitro stimulation with the T-dependent B-cell stimulus CD154. This along with the altered gene expression in AicdacreCd274fl/fl mice and αPD-L1-treated cells suggests a B cell-intrinsic role of PD-L1 in regulating B cell differentiation. Furthermore, PD-L1 expressed on B cell surface was tightly regulated during differentiation and internalized upon αPD-L1 treatment, suggesting a possible new mechanism on how PD-L1+ B cells modulate host immune responses. Supported by grants from NIH: The Ruth L. Kirschstein NRSA Institutional Research Training Grant (to MK), NIH T32 Graduate Research in Immunology Program (to CC), R01 AI153506 and R21 AI135599 (to ZX). Mays Cancer Center Dew Foundation Pilot Grant (to ZX) and DoD BCRP BC170448 (to ZX)