International Journal of Organ Transplantation Medicine T Helper Cells Fate Mapping by Co-stimulatory Molecules and its Functions in Allograft Rejection and Tolerance

T cell differentiation is dictated by a combination of T cell receptor (TCR) interaction with an antigen-bound major histocompatibility complex (MHC), and co-stimulatory molecules signal. The co-stimulatory signal can be positive or negative, and amplifying or diminishing the initial signal. However, the secondary co-stimulatory signal is not obligatory and its necessity is dictated, in part, by the stage of T cell development. In the field of transplantation, directing the T cell differentiation process can lead to therapeutic possibilities that promote allograft tolerance, and hinder unfavorable alloimmune responses. Therefore, understanding the details of T cell differentiation process, including the influence of co-stimulatory signals, is of paramount importance. It is important to note there is functional overlap between co-stimulatory molecules. It has been observed that some co-stimulatory signals have different effects on different T cell subsets. Hence, blockade of a co-stimulatory signal pathway, as part of a therapeutic regimen in transplantation, may have far reaching effects beyond the initial therapeutic intent and inhibit co-stimulatory signals necessary for desirable regulatory responses. In this review, co-stimulatory molecules involved in the differentiation of naïve T cells into T helper 1 (Th1), T helper 2 (Th2), T helper 17 (Th17), inducible regulatory T cells (iTregs), and T helper 9 (Th9) cells and their overlap are discussed. KEYWORD: T cell receptor; Receptors, Antigen, B-Cell; Major histocompatibility complex; Transplantation; Antigens, differentiation, T-lymphocyte; Transplantation tolerance; T-Lymphocytes, helper-inducer; T-Lymphocytes, regulatory *Correspondence: Rozita Abdoli, Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02445, USA E-mail: [email protected] INTRODUCTION Co-stimulatory pathways act synergistically to provide stimulatory and inhibitory signals that in combination with the T cell receptor-major histocompatibility complex (TCR-MHC) signal pathway activate naïve T cells. Activated naïve T cells are called effector cells. The effector cells may later develop into effector memory (EM) or central memory (CM) cells [1]. The co-stimulatory signals are critical for naïve T cell activation, and it has been shown that in the absence of these signals, TCR signal alone leads to T cell anergy, therefore, preventing an effective T cell response and promoting tolerance in vitro [2]. Knowledge of the co-stimulatory pathways is crucial in understanding the T cell immune response. The three major families of co-stimulatory Review Article