TFNR2 in Ischemia-Reperfusion Injury, Rejection, and Tolerance in Transplantation

Abstract

Tumor necrosis factor receptor 2 (TNFR2) has been shown to play a crucial role in CD4+ T regulatory cells (CD4+Tregs) expansion and suppressive function. Increasing evidence has also demonstrated its role in a variety of immune regulatory cell subtypes such as CD8+ T regulatory cells (CD8+ Tregs), B regulatory cells (Bregs), and myeloid-derived suppressor cells (MDSCs). In solid organ transplantation, regulatory immune cells have been associated with decreased ischemia-reperfusion injury (IRI), improved graft survival, and improved overall outcomes. However, despite TNFR2 being studied in the context of autoimmune diseases, cancer, and hematopoietic stem cell transplantation, there remains paucity of data in the context of solid organ transplantation and islet cell transplantation. Interestingly, TNFR2 signaling has found a clinical application in islet transplantation which could guide its wider use. This article reviews the current literature on TNFR2 expression in immune modulatory cells as well as IRI, cell, and solid organ transplantation. Our results highlighted the positive impact of TNFR2 signaling especially in kidney and islet transplantation. However, further investigation of TNFR2 in all types of solid organ transplantation are required as well as dedicated studies on its therapeutic use during induction therapy or treatment of rejection.

Leveraging the tolerogenic potential of TNF-α and regulatory B cells in organ transplantation

“…Increasing evidence supports TNFR2’s essential role in the proliferation and suppressive function of CD4 + Tregs, CD8 + Tregs, Myeloid-derived suppressor cells (MDSCs), and Bregs ( 45 ). In a study by Hijdra et al.…”

“…In a study by Hijdra et al. (2012), sarcoidosis patients with either steady disease or experiencing remission of the autoimmune symptoms exhibited an increased percentage of CD4 + TNFR2 + cells when compared to healthy individuals ( 45 ). This suggested the implication of TNFR2 signaling in down-regulating the immune system ( 45 ).…”

“…(2012), sarcoidosis patients with either steady disease or experiencing remission of the autoimmune symptoms exhibited an increased percentage of CD4 + TNFR2 + cells when compared to healthy individuals ( 45 ). This suggested the implication of TNFR2 signaling in down-regulating the immune system ( 45 ). As active TNFR2 + Treg cells surrounding tumors suppress anti-tumor CD8 + cytotoxic cells ( 46 ), cancer researchers have begun targeting this receptor with antagonistic therapies to inactivate Tregs and conversely foster cytotoxicity toward tumors.…”