Abstract
Absence of the mouse cell surface receptor SLAMF3 in SLAMF3-/- mice suggested that this receptor negatively regulates B cell homeostasis by modulating activation thresholds of B cell subsets. Here, we examine whether anti-SLAMF3 affects both B and T cell subsets during immune responses to haptenated ovalbumin [NP-OVA] and in the setting of chronic graft vs. host disease (cGVHD) induced by transferring B6.C-H2bm12/KhEg (bm12) CD4+ T cells into B6 WT mice. We find that administering αSLAMF3 to NP-OVA immunized B6 mice primarily impairs antibody responses and Germinal center B cell [GC B] numbers, whilst CXCR5+, PD-1+, and ICOS+ T follicular helper (TFH) cells are not significantly affected. By contrast, administering αSLAMF3 markedly enhanced autoantibody production upon induction of cGVHD by the transfer of bm12 CD4+ T cells into B6 recipients. Surprisingly, αSLAMF3 accelerated both the differentiation of GC B and donor-derived TFH cells initiated by cGVHD. The latter appeared to be induced by decreased numbers of donor-derived Treg and T follicular regulatory (TFR) cells. Collectively, these data show that control of anti-SLAMF3-induced signaling is requisite to prevent autoantibody responses during cGVHD, but reduces responses to foreign antigens.
Highlights
The signaling lymphocyte activation molecule family (SLAMF) of cell surface receptors, which consists of nine trans-membrane proteins (SLAMF1-9) serve as co-stimulatory molecules at immune synapses, are involved in viral and bacterial recognition and modulate myeloid and lymphocyte development [1]
SLAMF3-deficient mice develop autoantibodies irrespective of their genetic background, and as development several B cell subsets, e.g., Marginal zone [MZ] B cells are eliminated in these mice, we adopted a chronic graft vs. host disease (cGVHD) model to investigate the importance of SLAMF3 signaling in this disease
To this end we examined the effect of a mouse anti-mouseSLAMF3 monoclonal antibody on hapten-induced humoral responses and on autoantibody production in the bm12 CD4+ > B6 transfer model of cGVHD
Summary
The signaling lymphocyte activation molecule family (SLAMF) of cell surface receptors, which consists of nine trans-membrane proteins (SLAMF1-9) serve as co-stimulatory molecules at immune synapses, are involved in viral and bacterial recognition and modulate myeloid and lymphocyte development [1]. We previously found that the homophilic receptor SLAMF6 (Ly108, NTB-A) is implicated in the Germinal Center Reaction and that monoclonal antibodies directed against SLAMF6 reduce antibody responses to foreign antigens (Ags) and affect the number of auto-reactive B cells [2, 3]. Administering a mouse monoclonal antibody (mAb) directed against murine SLAMF3 (αSLAMF3) selectively eliminated splenic MZ B cells and significantly reduced the numbers of B1 and transitional 1 B cells in wild-type mice. Administering an agonistic anti-SLAMF3 mAb (Ly9.7.144) diminished both T cell-dependent and –independent antibody responses indicating a role for SLAMF3 dependent signaling in negative regulation of humoral immune responses. The concept of SLAMF3 as negative regulator of antibody responses was further supported by the finding that aged SLAMF3-deficient mice developed spontaneous autoantibodies against nuclear antigens [5, 6]
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