ABSTRACT
B cells have essential functions in multiple sclerosis and in its mouse model, experimental autoimmune encephalomyelitis, both as drivers and suppressors of the disease. The suppressive effects are driven by a regulatory B cell (Breg) population that functions, primarily but not exclusively, via the production of IL-10. However, the mechanisms modulating IL-10-producing Breg abundance are poorly understood. Here we identify SLAMF5 for controlling IL-10+ Breg maintenance and function. In EAE, the deficiency of SLAMF5 in B cells causes accumulation of IL10+ Bregs in the central nervous system and periphery. Blocking SLAMF5 in vitro induces both human and mouse IL-10-producing Breg cells and increases their survival with a concomitant increase of a transcription factor, c-Maf. Finally, in vivo SLAMF5 blocking in EAE elevates IL-10+ Breg levels and ameliorates disease severity. Our results suggest that SLAMF5 is a negative moderator of IL-10+ Breg cells, and may serve as a therapeutic target in MS and other autoimmune diseases.
Subject(s)
B-Lymphocytes, Regulatory/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Interleukin-10/immunology , Signaling Lymphocytic Activation Molecule Family/metabolism , Animals , Cell Survival/immunology , Cells, Cultured , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/immunology , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Multiple Sclerosis/immunology , Signaling Lymphocytic Activation Molecule Family/antagonists & inhibitors , Signaling Lymphocytic Activation Molecule Family/geneticsABSTRACT
Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) within the BM. The BM microenvironment supports survival of the malignant cells and is composed of cellular fractions that foster myeloma development and progression by suppression of the immune response. Despite major progress in understanding the biology and pathophysiology of MM, this disease is still incurable and requires aggressive treatment with significant side effects. CD84 is a self-binding immunoreceptor belonging to the signaling lymphocyte activation molecule (SLAM) family. Previously, we showed that CD84 bridges between chronic lymphocytic leukemia cells and their microenvironment, and it regulates T cell function. In the current study, we investigated the role of CD84 in MM. Our results show that MM cells express low levels of CD84. However, these cells secrete the cytokine macrophage migration inhibitory factor (MIF), which induces CD84 expression on cells in their microenvironment. Its activation leads to an elevation of expression of genes regulating differentiation to monocytic/granulocytic-myeloid-derived suppressor cells (M-MDSCs and G-MDSCs, respectively) and upregulation of PD-L1 expression on MDSCs, which together suppress T cell function. Downregulation of CD84 or its blocking reduce MDSC accumulation, resulting in elevated T cell activity and reduced tumor load. Our data suggest that CD84 might serve as a novel therapeutic target in MM.
Subject(s)
Multiple Myeloma/immunology , Signaling Lymphocytic Activation Molecule Family/genetics , Signaling Lymphocytic Activation Molecule Family/immunology , Signaling Lymphocytic Activation Molecule Family/metabolism , Tumor Microenvironment/immunology , Animals , B7-H1 Antigen , Cell Line, Tumor , Humans , Immunotherapy , Intramolecular Oxidoreductases/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Lymphocyte Activation , Macrophage Migration-Inhibitory Factors/metabolism , Mice , Multiple Myeloma/therapy , Myeloid-Derived Suppressor Cells/immunology , T-Lymphocytes/immunologyABSTRACT
Chronic lymphocytic leukemia (CLL) is a malignancy of mature B lymphocytes. The microenvironment of the CLL cells is a vital element in the regulation of the survival of these malignant cells. CLL cell longevity is dependent on external signals, originating from cells in their microenvironment including secreted and surface-bound factors. Dendritic cells (DCs) play an important part in tumor microenvironment, but their role in the CLL bone marrow (BM) niche has not been studied. We show here that CLL cells induce accumulation of bone marrow dendritic cells (BMDCs). Depletion of this population attenuates disease expansion. Our results show that the support of the microenvironment is partly dependent on CD84, a cell surface molecule belonging to the Signaling Lymphocyte Activating Molecule (SLAM) family of immunoreceptors. Our results suggest a novel therapeutic strategy whereby eliminating BMDCs or blocking the CD84 expressed on these cells may reduce the tumor load.
