CD4⁺CD25⁺ regulatory T cells in transplantation tolerance

Induction of transplantation tolerance to allogeneic grafts, defined as sustained alloantigen-specific unresponsiveness without the need of chronic immunosuppression, is one of the ultimate challenges in transplantation research. Multiple evidences indicate that the balance between alloaggressive and regulatory T cells is one of the key points in the decision to shift the balance towards graft rejection or immunological tolerance (pool size model of transplantation tolerance). Hence, the attainment of transplant tolerance requires both the deletion of a substantial proportion of alloreactive effector T cells, and the expansion of donor-specific immunoregulatory pathways. Immunoregulatory networks active in tolerant recipients are characterized by donor specificity, capacity to mediate linked suppression, and dependence on the indirect pathway of allorecognition. Several regulatory T cell subsets have been implicated in immunoregulatory phenomena in transplantation, but naturally occurring CD4⁺CD25⁺ regulatory T cells (T_Reg) appear to play a central role in allograft tolerance. Thus, tolerance cannot be adoptively transferred into immunodeficient recipients in the absence of CD4⁺CD25⁺ T cells among the tolerant lymphocytes. In addition, the depletion of CD4⁺CD25⁺ T cells before the administration of tolerogenic treatments can abolish the induction of tolerance. These effects appear to be mediated, at least in part, by the induction of an alloantigen-specific increase in the immunoregulatory properties of CD4 ⁺CD25⁺ T cells. However, the capacity of CD4 ⁺CD25⁺ T cells to mediate other major features of allograft tolerance such as linked suppression and infectious tolerance is still unknown. There also lacks a clear understanding on how CD4⁺CD25 ⁺ T cells interact with other regulatory T cell subsets active in transplant tolerance.