A naturally occurring CD8^＋CD122^＋ T-cell subset as a memory-like Treg family

Despite extensive studies on CD4^＋CD25^＋ regulatory T cells （Tregs） during the past decade, the progress on their clinical translation remains stagnant. Mounting evidence suggests that naturally occurring CD8^＋CD122^＋ T cells are also Tregs with the capacity to inhibit T-cell responses and suppress autoimmunity as well as alloimmunity. In fact, they are memory-like Tregs that resemble a central memory T cell （TcM） phenotype. The mechanisms underlying their suppression are still not well understood, although they may include IL-IO production. We have recently demonstrated that programmed death-1 （PD-1） expression distinguishes between regulatory and memory CD8^＋CD122^＋ T cells and that CD8^＋CD122^＋ Tregs undergo faster homeostatic proliferation and are more potent in the suppression of allograft rejection than conventional CD4^＋CD25^＋ Tregs. These findings may open a new line of investigation for accelerating effective Treg therapies in the clinic. In this review, we summarize the significant progress in this promising field of CD8^＋CD122^＋ Treg research and discuss their phenotypes, suppressive roles in autoimmunity and alloimmunity, functional requirements, mechanisms of action and potential applications in the clinic.

Functions of p53 in pluripotent stem cells

Pluripotent stem cells(PSCs)are capable of unlimited self-renewal in culture and differentiation into all functional cell types in the body,and thus hold great promise for regenerative medicine.To achieve their clinical potential,it is critical for PSCs to maintain genomic stability during the extended proliferation.The critical tumor suppressor p53 is required to maintain genomic stability of mammalian cells.In response to DNA damage or oncogenic stress,p53 plays multiple roles in maintaining genomic stability of somatic cells by inducing cell cycle arrest,apoptosis,and senescence to prevent the passage of genetic mutations to the daughter cells.p53 is also required to maintain the genomic stability of PSCs.However,in response to the genotoxic stresses,a primary role of p53 in PSCs is to induce the differentiation of PSCs and inhibit pluripotency,providing mechanisms to maintain the genomic stability of the self-renewing PSCs.In addition,the roles of p53 in cellular metabolism might also contribute to genomic stability of PSCs by limiting oxidative stress.In summary,the elucidation of the roles of p53 in PSCs will be a prerequisite for developing safe PSC-based cell therapy.

Role of CD8^(+) regulatory T cells in organ transplantation

CD8^(+)T cells are regulatory T cells(Tregs)that suppress both alloimmunity and autoimmunity in many animal models.This class of regulatory cells includes the CD8^(+)CD28^(-),CD8^(+)CD103^(+),CD8^(+)FoxP3^(+)and CD8^(+)CD122^(+)subsets.The mechanisms of action of these regulatory cells are not fully understood;however,the secretion of immunosuppressive cytokines,such as interleukin(IL)-4,IL-10 and transforming growth factor beta(TGF-β)as well as the direct killing of target cells via Fas L/Fas and the perforin/granzyme B pathways have been demonstrated in various models.Further studies are necessary to fully understand the mechanisms underlying the suppressive effects of Tregs and to provide experimental support for potential clinical trials.We recently observed that CD8^(+)CD122^(+)Tregs more potently suppressed allograft rejection compared to their CD4^(+)CD25^(+)counterparts,supporting the hypothesis that CD8^(+)Tregs may represent a new and promising Treg family that can be targeted to prevent allograft rejection in the clinic.In this review,we summarize the progress in the field during the past 7-10 years and discuss CD8^(+)Treg phenotypes,mechanisms of action,and their potential clinical applications;particularly in composite tissue transplants in burn and trauma patients.