Role of TNF-TNF Receptor 2 Signal in Regulatory T Cells and Its Therapeutic Implications.

Tumor necrosis factor α (TNFα) is a pleiotropic cytokine which signals through TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Emerging evidence has demonstrated that TNFR1 is ubiquitously expressed on almost all cells, while TNFR2 exhibits a limited expression, predominantly on regulatory T cells (Tregs). In addition, the signaling pathway by sTNF via TNFR1 mainly triggers pro-inflammatory pathways, and mTNF binding to TNFR2 usually initiates immune modulation and tissue regeneration. TNFα plays a critical role in upregulation or downregulation of Treg activity. Deficiency in TNFR2 signaling is significant in various autoimmune diseases. An ideal therapeutic strategy for autoimmune diseases would be to selectively block the sTNF/TNFR1 signal through the administration of sTNF inhibitors, or using TNFR1 antagonists while keeping the TNFR2 signaling pathway intact. Another promising strategy would be to rely on TNFR2 agonists which could drive the expansion of Tregs and promote tissue regeneration. Design of these therapeutic strategies targeting the TNFR1 or TNFR2 signaling pathways holds promise for the treatment of diverse inflammatory and degenerative diseases.

In Vivo Attenuation of Antibody-Mediated Acute Renal Allograft Rejection by Ex Vivo TGF-ß-Induced CD4+Foxp3+ Regulatory T Cells.

Antibody-mediated rejection (AMR) has emerged as the major cause of renal allograft dysfunction, and more effective strategies need to be explored for improving transplant outcomes. Regulatory T cells (Tregs), consisting of at least natural and induced Treg subsets, suppress effector responses at multiple levels and play a key role in transplantation tolerance. In this study, we investigated the effect of induced Tregs (iTregs) on preventing antibody-mediated renal injury and rejection in a mouse model. We observed that infusion of iTregs markedly attenuated histological graft injury and rejection and significantly improved renal allograft survival. iTregs exhibited a comprehensive ability to regulate immunological disorders in AMR. First, iTreg treatment decreased the levels of circulating antidonor antibody and the antibody deposition within allografts. Second, iTregs significantly reduced cell infiltration including CD4+ T cells (including Th1, Th17, and Tfh), CD8+IFN-γ+ cells, natural killer cells, B cells, and plasma cells, which are involved in the process of AMR. Our results also highlight a predominance of M1 macrophage infiltration in grafts with acute AMR, and M1 macrophage could be reduced by iTreg treatment. Collectively, our data demonstrate, for the first time, that TGF-ß-induced Tregs can attenuate antibody-mediated acute renal allograft injury through targeting multiple effectors. Thus, use of iTregs in prevention of AMR in clinical practice could be expected.