Innate immune cells may regulate adaptive immunity by balancing different lineages of T cells and providing negative costimulation. In addition, CD11b+Gr-1+ myeloid-derived suppressor cells have been described in tumor, parasite infection, and severe trauma models. In this study, we observe that splenic CD11b+ cells markedly increase after experimental autoimmune encephalomyelitis (EAE) immunization, and they suppress T cell proliferation in vitro. Although >80% of CD11b+ cells express varying levels of Gr-1, only a small population of CD11b+Ly-6Chigh inflammatory monocytes (IMC) can efficiently suppress T cell proliferation and induce T cell apoptosis through the production of NO. IFN-γ produced by activated T cells is essential to induce IMC suppressive function. EAE immunization increases the frequencies of IMC in the bone marrow, spleen, and blood, but not in the lymph nodes. At the peak of EAE, IMC represent ∼30% of inflammatory cells in the CNS. IMC express F4/80 and CD93 but not CD31, suggesting that they are immature monocytes. Furthermore, IMC have the plasticity to up-regulate NO synthase 2 or arginase 1 expression upon different cytokine treatments. These findings indicate that CD11b+Ly-6Chigh IMC induced during EAE priming are powerful suppressors of activated T cells. Further understanding of suppressive monocytes in autoimmune disease models may have important clinical implications for human autoimmune diseases.

CD20 mAb-mediated B cell depletion is an effective treatment for B cell malignancies and some autoimmune diseases. However, the full effects of B cell depletion on natural, primary, and secondary Ab responses and the maintenance of Ag-specific serum Ig levels are largely unknown. The relationship between memory B cells, long-lived plasma cells, and long-lived humoral immunity also remains controversial. To address the roles of B cell subsets in the longevity of humoral responses, mature B cells were depleted in mice using CD20 mAb. Peritoneal B cell depletion reduced natural and Ag-induced IgM responses. Otherwise, CD20+ B cell depletion prevented humoral immune responses and class switching and depleted existing and adoptively transferred B cell memory. Nonetheless, B cell depletion did not affect serum Ig levels, Ag-specific Ab titers, or bone marrow Ab-secreting plasma cell numbers. Coblockade of LFA-1 and VLA-4 adhesion molecules temporarily depleted long-lived plasma cells from the bone marrow. CD20+ B cell depletion plus LFA-1/VLA-4 mAb treatment significantly prolonged Ag-specific plasma cell depletion from the bone marrow, with a significant decrease in Ag-specific serum IgG. Collectively, these results support previous claims that bone marrow plasma cells are intrinsically long-lived. Furthermore, these studies now demonstrate that mature and memory B cells are not required for maintaining bone marrow plasma cell numbers, but are required for repopulation of plasma cell-deficient bone marrow. Thereby, depleting mature and memory B cells does not have a dramatic negative effect on preexisting Ab levels.

Inflammation removes developing and mature lymphocytes from the bone marrow (BM) and induces the appearance of developing B cells in the spleen. BM granulocyte numbers increase after lymphocyte reductions to support a reactive granulocytosis. Here, we demonstrate that inflammation, acting primarily through tumor necrosis factor ␣ (TNF ␣ ), mobilizes BM lymphocytes. Mobilization reflects a reduced CXCL12 message and protein in BM and changes to the BM environment that prevents homing by cells from naive donors. The effects of TNF ␣ are potentiated by interleukin 1 ␤ (IL-1 ␤ ), which acts primarily to expand the BM granulocyte compartment. Our observations indicate that inflammation induces lymphocyte mobilization by suppressing CXCL12 retention signals in BM, which, in turn, increases the ability of IL-1 ␤ to expand the BM granulocyte compartment. Consistent with this idea, lymphocyte mobilization and a modest expansion of BM granulocyte numbers follow injections of pertussis toxin. We propose that TNF ␣ and IL-1 ␤ transiently specialize the BM to support acute granulocytic responses and consequently promote extramedullary lymphopoiesis.