B1 B cells are the major source of natural antibody that is essential for innate immunity. The B1 repertoire is skewed toward production of phosphatidylcholine (PtC)-binding V H 11 and V H 12 immunoglobulin that plays a key role in immune defense against bacterial infection. Programmed death-ligand 2 (PD-L2) is a ligand for the immunosuppressive receptor programmed death-1 (PD-1). It has been reported that expression of PD-L2 is restricted to dendritic cells and macrophages in mice. Here we show that 50-70% of resting peritoneal B1 cells express PD-L2, which is not present or inducible on conventional B2 B cells or PD-L2 -B1 cells. Although PD-L2 + and PD-L2 -B1 cells are similar in proliferative responses and spontaneous immunoglobulin secretion, PD-L2 + B1 cells are highly enriched for expression of V H 11 and V H 12 genes and encompass the bulk of PtC-binding B1 cells. These findings extend the range of known PD-L2 expression to B cells and show that B1 cells identified by this marker express a specific repertoire associated with anti-bacterial immunity. IntroductionB1 B cells comprise a unique subset of B cells distinguished phenotypically, ontogenetically, and functionally from conventional (B2) B cells [1][2][3]. B1 B cells are the major source of natural immunoglobulin in normal unimmunized mice, providing a vital front line defense against bacterial and viral infection [4][5][6][7][8]. This function is associated with a skewed repertoire containing autoreactive specificities, one manifestation of which is expression of phosphatidylcholine (PtC)-binding V H 11 and V H 12 by a substantial portion of peritoneal B1 cells in unimmunized mice [9][10][11]. PtC is the polar headgroup of common membrane phospholipids. Reconstitution of anti-PtC IgM in sIgM-deficient mice substantially reduced the bacterial load in a cecal ligation and puncture model [5]. Thus, V H 11/V H 12-expressing B1 cells play an important role in immunity; considering that PtC-binding B1 cells recognize protease-treated autologous erythrocytes, they may play a role in hemolytic autoimmune dyscrasias as well [10,12].B cells, like T cells, express programmed death-1 (PD-1), engagement of which negatively regulates B cell activity in vitro [13]. Surface levels of PD-1 are upregulated by BCR stimulation and down-regulated by Results and discussionPeritoneal B1 cells uniquely express PD-L2To evaluate PD-L1 and PD-L2 expression, cells from normal peritoneal washout fluids and spleens were stained with fluorescent antibodies to identify B1 cells, B2 cells and T cells and were counterstained to detect PD-L1 and PD-L2. Like B2 cells and T cells, B1 cells expressed a basal level of PD-L1, although to a much greater extent (Fig. 1A). Surprisingly, we found that a significant portion of peritoneal B1 cells (50-70%) expressed PD-L2, whereas B2 cells and T cells failed to do so (Fig. 1A). A smaller and less distinct population of splenic B1 cells also expressed PD-L2. To exclude the possibility of staining artifacts, we sorted PD-L2 + and PD-L2 -periton...
Regulatory T (T reg ) cells are indispensable for maintaining peripheral tolerance, whereas T helper (Th)1 and Th17 cells induce inflammation and tissue destruction. Using Foxp3-GFP knock-in mice, we report a novel regulatory role for B cell subsets in influencing the differentiation of T reg versus Th1/Th17 cells. Peritoneal B1 cells strongly promoted T cell proliferation and cytokine secretion when presenting nominal or allogeneic antigens, as compared to conventional follicular B (B2) cells. However, peritoneal B1 cells largely failed to convert naive Foxp3 -CD4 + T cells into Foxp3 + T reg cells in the presence of TGF-b and IL-2, in marked contrast to conventional B2 cells, which excelled in T reg conversion. Interestingly, under the same T reg conversion conditions, peritoneal B1 cells preferentially promoted Th1 and Th17 cell differentiation. Blockade of CD86 but not CD80 costimulation markedly enhanced T reg cell induction by B1 cells. Thus, B cell antigen presentation function is inversely correlated with de novo T reg cell induction for these B cell subsets. Our findings suggest that B1 and B2 cell subsets play distinct roles in immune regulation by promoting reciprocal differentiation of T cell lineages.
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