T helper subsets & regulatory T cells: rethinking the paradigm in the clinical context of solid organ transplantation

Recent years have witnessed remarkable expansion in the knowledge of how various immune/inflammatory cells and T helper (Th) cell subsets, including Th1, Th2, Th9, Th17, Th22, follicular T helper (Tfh) and Treg subpopulations, reciprocally regulate each other. This review highlights current understanding of the Th subsets paradigm, who are the old school players, who are the new kids on the block and how does each come to play in different clinical contexts in solid organ transplantation. The article commences with a brief overview of the development and characteristic cytokine profiles of individual members of the paradigm. However, the main focus of this review is on the current understanding of the Th subset paradigm, and how these unique subpopulations impact host responses towards solid organ allografts. More specifically, it will highlight the recent findings that implicate the paradigm in transplantation. The interplay among different subsets is discussed collectively in the clinical context of pretransplant immunological risk factors such as alloimmunization as well as post-transplant immunological consequences such as rejection. Accumulating evidence suggests that Th17 cells play a role in the development of chronic allograft injury in transplantation of various organs. In vitro, tacrolimus suppressed Th1 and Th2 cells but not Th17 cells. Animal studies suggest that regulatory T cells (Treg)-based therapies could be effective as mechanisms of long-term drug-free transplant tolerance in humans. Indeed, a dual role for TGF-β and Foxp3 in induced tolerance has been proposed, in which TGF-β stimulates Foxp3 expression and is associated with the induction of Treg-facilitating acquisition of tolerance. Exploiting Th subsets' regulatory functions could potentially offer opportunities for immunological interventions in solid organ transplantation.