Distinct modes of TNF signaling through its two receptors in health and disease.

TNF is a key proinflammatory and immunoregulatory cytokine whose deregulation is associated with the development of autoimmune diseases and other pathologies. Recent studies suggest that distinct functions of TNF may be associated with differential engagement of its two receptors: TNFR1 or TNFR2. In this review, we discuss the relative contributions of these receptors to pathogenesis of several diseases, with the focus on autoimmunity and neuroinflammation. In particular, we discuss the role of TNFRs in the development of regulatory T cells during neuroinflammation and recent findings concerning targeting TNFR2 with agonistic and antagonistic reagents in various murine models of autoimmune and neuroinflammatory disorders and cancer. ©2020 Society for Leukocyte Biology.