Hepatic Stellate Cells Directly Inhibit B Cells via Programmed Death–Ligand 1

Abstract

We previously demonstrated that mouse hepatic stellate cells (HSCs) suppress T cells via programmed death-ligand 1 (PD-L1), but whether HSCs exert any effects on B cells, the other component of the adaptive immune system, remains unknown. In this study, we found that mouse HSCs directly inhibited B cells and that PD-L1 was also integrally involved. We found that (a) HSCs inhibited the upregulation of activation markers on activated B cells; (b) HSCs inhibited the proliferation of activated B cells and their cytokine/immunoglobulin production in vitro; and (c) pharmaceutically or genetically blocking the interaction of PD-L1 with programmed death-1 (PD-1) impaired the ability of HSCs to inhibit B cells. To test the newly discovered B-cell-inhibitory activity of HSCs in vivo, we developed a protocol of intrasplenic artery injection to directly deliver HSCs into the spleen. We found that local delivery of wild-type HSCs into the spleens of mice that had been immunized with 4-hydroxy-3-nitrophenylacetyl-Ficoll, a T-cell-independent antigen, significantly suppressed antigen-specific IgM and IgG production in vivo, whereas splenic artery delivery of PD-L1-deficient HSCs failed to do so. In conclusion, in addition to inhibiting T cells, mouse HSCs concurrently inhibit B cells via PD-L1. This direct B-cell-inhibitory activity of HSCs should contribute to the mechanism by which HSCs maintain the liver’s immune homeostasis.

B cells induced by Schistosoma japonicum infection display diverse regulatory phenotypes and modulate CD4+ T cell response

“…Although PD1 signaling in B cells has been demonstrated to inhibit the proliferation and cytokine production of activated B cells [56], we did not find the effects of systematic PD-L1 blocking on the proportion of B-1a cells and cytokine production in splenic B cells during S. japonicum infection. PD-L1 blocking in mice after infection only reduced PD-L1 MFI of splenic B cells from infected mice, and this might be because treatment with anti-PD-L1 antibody in vivo affected the binding of fluorescent antibodies to PD-L1.…”

2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection

“…Putative chronic AMR lesions are also associated with microvascular endothelial C4d deposition in most studies, but diffuse intense microvascular inflammation is less common than in acute AMR (). This might be related to lower antibody production because of activated B cell deletion via a PD‐L1‐mediated mechanism or others.…”

Immunological Determinants of Liver Transplant Outcomes Uncovered by the Rat Model

“…[11][12][13][14][15][16][17][18][19][20] Professional antigen-presenting cells (APCs), such as DCs and KCs, and nonprofessional APCs, such as LSECs and hepatic stellate cells, not only favor the development of T reg in detriment of cytotoxic T lymphocytes but also promote clonal anergy and deletion of effector T and B cells. 11,[21][22][23][24][25][26] This response can be attributed mainly to the upregulation of inhibitory signals, such as programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and the low levels of the major histocompatibility complex (MHC) class I and of costimulatory molecules in the liver. 21,22,24 The inherent tolerogenic state of the liver reflects in less stringent criteria for matching LT donors and recipients when compared with other solid organs.…”