MZ B cells usually develop later than additional B cell subsets in mice [112]. effector T cells. If B cells are absent or greatly reduced in quantity, additional APC will present the antigen, such that Treg are preferentially triggered and effector T cells are not triggered. In these situations, B?/? or B cell-depleted mice develop the autoimmune disease when T regulatory cells (Treg) are transiently depleted. This review focuses on how B cells influence Treg activation and function, and briefly considers factors that influence the effectiveness of B cell depletion for treatment of autoimmune diseases. 0.01; *** 0.001, n.s., not significant. Results are the mean SAT severity scores from individual recipient mice. Observe [63] for more details. Our experiments showed that Treg in WT and B?/? mice, in addition to differing in function, experienced significant variations in cell surface expression of several molecules, including glucocorticoid induced tumor necrosis element related protein (GITR), Tumor Necrosis Element Receptor II (TNFRII) and CD27 [65]. Importantly, if T cells from B?/? mice developed from bone marrow precursors in the presence of bone marrow from B cell-positive mice, Treg experienced the phenotype of WT Treg and not Treg from B?/? mice [65]. Regrettably, efforts to correlate the phenotypic variations with variations in function were not successful. In the mouse model of experimental arthritis where Treg from B?/? mice had increased function compared to Treg from WT mice, production of Interferon (IFN)- by B cells was reported to be responsible for the inhibition of Treg function and development of more severe arthritis [53]. These results are of particular interest because IFN- is usually a proinflammatory cytokine, and other proinflammatory cytokines such as IL-6 [66,67], IL-2 [66], granulocyte macrophage colony stimulating factor (GM-CSF) [30] and TNF- [68], all of which can be produced by B cells, can interfere with Treg function and could contribute to increased Teff activation when B cells are present. B cell production of IFN- or other proinflammatory cytokines could contribute to the ability of B cells to function as effective APC for activation of autoreactive Teff Hyperforin (solution in Ethanol) [66]. B cells also express molecules such as GITR-L which can block Treg expansion or function in some models [69,70,71,72]. However, GITR-L Hyperforin (solution in Ethanol) expressed on B cells was also reported to maintain Tregs at a level sufficient to inhibit EAE [25], and GITR can be a marker for functional Treg [73]. Therefore, signaling through GITR can have different outcomes depending on the environment and/or activation state of Treg and Teff [71]. In most autoimmune disease models, T cells in B?/? mice will usually be in a less inflammatory environment than they are in B cell-positive mice, and the inflammatory environment may be a major factor in determining the differential functions of Treg in WT vs. B?/? mice. When the inflammatory environment is usually high, Breg can become activated in an attempt to downregulate the inflammation, e.g., by producing anti-inflammatory cytokines such as IL-10 and IL-35 [74,75,76]. Cytokines produced by Breg inhibit activation or expansion of Teff, and can promote expansion of Treg [31,77,78,79]. Therefore, Breg play an important NOX1 role in dampening autoimmunity in several different models, most notably in EAE where they have been extensively studied [26,31,77,79,80]. Overall, these results suggest that B cells and/or specific molecules produced or expressed by B cells can both inhibit and promote Treg function in some autoimmune disease models. Further studies are needed to determine the specific cytokines or cell surface molecules that are most important in this regard. 6. Transient Depletion of Treg Is Sufficient to Result in Autoimmune Disease in B?/? Mice Because Tregs That Repopulate Following Depletion Have Reduced Function The fact that Treg depletion results in development of autoimmune diseases in B?/? mice that are normally resistant to those diseases is perhaps not unexpected given that mice lacking Treg due to absence of Foxp3+ T cells spontaneously develop several organ-specific autoimmune diseases and die at a young age [43,81]. In the studies described above, where Treg depletion leads to autoimmune disease Hyperforin (solution in Ethanol) in B?/? mice that normally do not develop the disease, the situation is different. First, administration of anti-CD25 generally results in reduction of CD25+CD4+ T cells for less than 2 weeks [5,34,41,65]. In some studies, anti-CD25 reduced both CD25+ and Foxp3+ cells suggesting that Tregs are actually depleted [5,14,42,65], whereas another study showed that anti-CD25 did not deplete Foxp3+ cells but functionally inactivated them [82]. In any.