MDSCs are a heterogeneous group of myeloid cells that suppress T cell activity in cancer and autoimmune disease. The effect of MDSCs on B cell function is not clear. Using the CIA model of autoimmune disease, we found an increase in M-MDSCs in the periphery of WT mice with CIA compared with naïve mice. These MDSCs were absent from the periphery of CCR2(-/-) mice that developed exacerbated disease. M-MDSCs, isolated from immunized mice, inhibited autologous CD4(+) T cell proliferation. The M-MDSC-mediated suppression of T cell proliferation was NO and IFN-γ dependent but IL-17 independent. Furthermore, we demonstrated for the first time that M-MDSCs from CIA mice also inhibited autologous B cell proliferation and antibody production. The suppression of B cells by M-MDSCs was dependent on the production of NO and PGE2 and required cell-cell contact. Administration of M-MDSCs rescued CCR2(-/-) mice from the exacerbated CIA phenotype and ameliorated disease in WT mice. Furthermore, adoptive transfer of M-MDSCs reduced autoantibody production by CCR2(-/-) and WT mice. In summary, M-MDSCs inhibit T cell and B cell function in CIA and may serve as a therapeutic approach in the treatment of autoimmune arthritis.

Myeloid-derived suppressor cells (MDSCs) represent an important class of immunoregulatory cells that can be activated to suppress T cell functions. These MDSCs can inhibit T cell functions through cell surface interactions and the release of soluble mediators. MDSCs accumulate in the inflamed tissues and lymphoid organs of patients with autoimmune diseases. Much of our knowledge of MDSC function has come from studies involving cancer models, however many recent studies have helped to characterize MDSC involvement in autoimmune diseases. MDSCs are a heterogeneous group of immature myeloid cells with a number of different functions for the suppression of T cell responses. However, we have yet to fully understand their contributions to the development and regulation of autoimmune diseases. A number of studies have described beneficial functions of MDSCs during autoimmune diseases, and thus there appears to be a potential role for MDSCs in the treatment of these diseases. Nevertheless, many questions remain as to the activation, differentiation, and inhibitory functions of MDSCs. This review aims to summarize our current knowledge of MDSC subsets and suppressive functions in tissue-specific autoimmune disorders. We also describe the potential of MDSC-based cell therapy for the treatment of autoimmune diseases and note some of hurdles facing the implementation of this therapy.

West Nile virus (WNV) employs several different strategies to escape the innate immune response. We have previously demonstrated that the WNV NS1 protein interferes with signal transduction from Toll-like receptor 3 (TLR3). NS1 is a glycoprotein that can be found intracellularly or associated with the plasma membrane. In addition, NS1 is secreted to high levels during flavivirus infections. We investigated whether the secreted form of NS1 inhibits innate immune signaling pathways in uninfected cells. Secreted NS1 (sNS1) was purified from supernatants of cells engineered to express the protein. Purified sNS1 associated with and repressed TLR3-induced cytokine production by HeLa cells, and inhibited signaling from TLR3 and other TLRs in bone marrow-derived macrophages and dendritic cells. Footpad administration of sNS1 showed the protein associated predominantly with macrophages and dendritic cells in the draining lymph node. Additionally, sNS1 significantly reduced TLR3 signaling and WNV replicon particle-mediated cytokine transcription in popliteal lymph nodes.

Abnormal B- and T-cell recognition of self-antigens and autoantibody production result in autoimmunity. We previously showed that myeloid-derived suppressor cells (MDSCs) suppress T cell proliferation in autoimmune arthritis. To further explore the impact of MDSCs on B cells, we examined B cell functions in vitro and in vivo in collagen-induced arthritis. We found the proliferation of collagen-primed B cells was inhibited by autologous monocytic MDSCs, but not by Ly6G+ neutrophils. The production of both IgG and IgM was reduced in the supernatant of B cell and monocytic MDSC co-cultures as compared to the supernatant from B cells alone or the supernatant from B cell-Ly6G+ cell co-cultures. Mechanistically, the levels of iNOS and PGE2 increased in the B cell-MDSC co-cultures, and addition of either iNOS or PGE2 inhibitors abolished the MDSC suppression of B cell proliferation. While neutralizing IL-12 also reestablished B cell proliferation, blockade of IL-6 and TNFa did not show similar effect. Finally, adoptive transfer of monocytic MDSCs to collagen-immunized mice resulted in reduced autoantibody production and mitigated arthritis severity. In summary our data show that monocytic MDSCs suppress autoreactive B cell proliferation and antibody production. The suppressive function requires iNOS, PGE2 and IL-12, but is independent of IL-6 and TNFa. These MDSCs can potentially be used in cell-based therapy to treat autoimmune arthritis by limiting B cell functions.

Myeloid-derived suppressor cells (MDSCs) are subtypes of monocytes and granulocytes that suppress T cell activity in diseases like cancer and multiple sclerosis. Our previous studies suggested a subset of monocytes may act as MDSCs in autoimmune arthritis. Using the collagen-induced arthritis (CIA) model we identified an increase in the Ly6Chigh subset of monocytes in the periphery of WT mice with CIA compared to naïve mice. This subset was absent from the periphery of CCR2-deficient mice and these mice developed more severe CIA disease. Ly6Chigh monocytes isolated from immunized mice inhibited collagen-activated CD4+T cell proliferation as well as reduced the overall T cell numbers. In the presence of Ly6Chigh monocytes we observed high levels of nitric oxide in the supernatants and an increase in Annexin V positive CD4+T cells. To examine the biological role of these monocytes, we performed a cell-based treatment assay. Compared to control mice, in vivo transfer of Ly6Chigh monocytes to collagen-immunized mice resulted in delayed onset of disease, reduced joint swelling, decreased IL-6, IL-1β, and IFNγ expression in the joints and decreased IL-6 and IL-17 levels in the serum. In summary, Ly6Chigh monocytes function as MDSCs to inhibit CD4+T cell proliferation and survival. In vivo transfer of Ly6Chigh monocytes ameliorated autoimmune arthritis in the CIA model suggesting these cells could potentially be used in cell-based therapies for treatment of rheumatoid arthritis.