PD-L1/PD-L2-expressing B-1 cells inhibit alloreactive T cells in mice

Abstract

B cells constitute a complex system of antigen-presenting cells (APCs) and exist as distinct subsets that differ in their lineage affiliation, surface molecule expression, and biological function, thus potentially regulating the immune response. In this study, we investigated the immune-regulatory roles of murine B cell subsets as regulatory APCs targeting alloreactive T cells. Either splenic B cells, peritoneal cavity (PerC) B cells, or non-B cells from Balb/c mice were intravenously injected into B6 mice. Serum levels of anti-Balb/c antibodies in the recipients of PerC B cells were significantly lower than those in the recipients of splenic B cells and PerC non-B cells, as determined over a 4-week period after the injection. Mixed-lymphocyte reaction (MLR) assays using splenocytes from the B6 mice at 2 weeks after the injection revealed the significantly reduced anti-Balb/c T cell-responses in the recipients of PerC B cells, as compared to those in the recipients of splenic B cells or untreated control mice. Since PerC B cells contained MHC class II+ CD80+ CD86+ PD-L1+ PD-L2+ cells among the CD5+ B-1a cell subset, PerC B cells from Balb/c mice were pre-incubated with anti-PD-L1/PD-L2 mAbs prior to injection. This treatment abrogated their immune-regulatory effects on anti-Balb/c T cells in the MLR assays. In addition, the inoculation with Balb/c PerC B cells significantly prolonged the survival of subsequently grafted Balb/c hearts in B6 mouse recipients, whereas that with SPL B cells did not. These findings indicate that the PerC B cells, including PD-L1/PD-L2 B-1a cells, may suppress T cells responding to allostimulation, and thus may be optimal for donor lymphocyte injection.

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

“…PD-L1 expression in splenic B cells was elevated during acute and chronic infection, whereas the expression of PD-L1 in PerC B cells was decreased during chronic schistosomiasis. The difference in PD-L1 expression of B cells during infection might be due to the higher basic level of PD-L1 in PerC B cells compared to that in splenic B cells [45] and the infection-induced migration of PerC B-1a cells to the liver [46].…”

B cells in esophago-gastric adenocarcinoma are highly differentiated, organize in tertiary lymphoid structures and produce tumor-specific antibodies

“…Immunosuppressive B cell subsets, which inhibit immune responses by production of Interleukin-10 (IL-10), Granzyme B or expression of PD-L1 have been described. [22][23][24][25] However, in our study regulatory B cell subsets (CD24 ++ CD38 ++ or CD24 high CD27 + in % of CD 19 + CD20 + ) were not increased in tumor samples (1.6% ± 0.3 and 10.1% ± 2.0) compared to TDLN (0.5% ± 0.1 and 5.3% ± 1.1, p = 0.4 and 0.1), PBMC of EAC patients (3.1% ± 0.5 and 18.5% ± 2.1, p < 0.05) and PBMC of healthy controls (3.1% ± 0.4 and 20.0% ± 2.2, p < 0.05 and 0.2; Supplementary Figure 3A, B). In addition, PD-L1 + B cells were not enriched in the tumor microenvironment (1.9% ± 0.4) compared to PBMC AC (1.8% ± 0.3, p = 1.0) and PBMC HC (1.0% ± 0.1, respectively, p = 0.9, Supplemetary Figure 3C).…”

Regulatory B cells and advances in transplantation

“…Hirose et al. demonstrated that PD‐L1 and PD‐L2 expressed by peritoneal cavity B‐1a cells mediated a reduction in CD4 + and CD8 + T cells in mice through interaction with PD‐1, whereas blocking PD‐L1 and PD‐L2 led to an increase in CD4 + and CD8 + T cells …”

“…ligand (FasL),[48][49][50][51] TRAIL,52,53 and programmed death-ligand (PD-L) 1 and 2,[54][55][56][57][58] all of which can initiate the programmed cell death of target cells 39. The interaction of FasL, expressed by B cells, with the Fas receptor can initiate a signaling cascade that leads to Th cell apoptosis48,49 ;Th cell apoptosis induced by B cells was first directly demonstrated by using FasL + B cells to kill CD4 + T cells 50.…”

“…B cell-derived PD-L1 and PD-L2 can deliver death signals to PD-1 + T cells, thereby inhibiting T cell activation, encouraging immune homeostasis, and mediating tolerance [54][55][56][57]. Hirose et al demonstrated that PD-L1 and PD-L2 expressed by peritoneal cavity B-1a cells mediated a reduction in CD4 + and CD8 + T cells in mice through interaction with PD-1, whereas blocking PD-L1 and PD-L2 led to an increase in CD4 + and CD8 + T cells 58.…”