Here we discuss the role TNF-α plays in the pathogenesis of many autoimmune diseases and their relation to Breg suppressive function with the ultimate goal of designing a combinatorial therapy involving blocking the TNFR1 receptor associated with inflammatory TNF-α signaling, activation of TNFR2 signaling involved with an anti-inflammatory response, and TLR-Bregs to suppress effector T cell proliferation and induce regulatory T cells. Here, TNF is linked to autoimmune disease.