Despite extensive studies on CD4þCD25þ regulatory T cells (Tregs), their application in adoptive transfer therapies is still not optimal in immune-competent wild-type (WT) animal models. Therefore, it is compelling to search for more potent Tregs for potential clinical application. Mounting evidence has shown that naturally occurring CD8þCD122þ T cells are also Tregs. However, their suppression in allograft rejection, efficiency in suppression and underlying mechanisms remain unclear. Using a murine allotransplantation model, we reported here that CD8þCD122þ Tregs were actually more potent in suppression of allograft rejection and underwent more rapid homeostatic proliferation than their CD4þCD25þ counterparts. Moreover, they produced more IL-10 and were more potent in suppressing T cell proliferation in vitro. Deficiency in IL-10 in CD4þCD25þ and CD8þCD122þ Tregs resulted in their reduced but equal suppression in vivo and in vitro, suggesting that IL-10 is responsible for more effective suppression by CD8þCD122þ than CD4þCD25þ Tregs. Importantly, transfer of CD8þCD122þ Tregs together with the administration of recombinant IL-15 significantly prolonged allograft survival in WT mice. Thus, for the first time, we demonstrate that naturally arising CD8þCD122þ Tregs not only inhibit allograft rejection but also exert this suppression more potently than their CD4þCD25þ counterparts. This novel finding may have important implications for tolerance induction.
Cigarette smoke causes cancer and increases the vulnerability of smokers to infections. Epidemiologic studies have shown that smoking is one of major risk factors for late allograft rejection. Despite statistical data that associate smoking with allograft rejection, no any study has been conducted to prove that cigarette smoke directly causes allograft rejection in a cause-effect manner. In particular, investigation into immunologic mechanisms underlying smoke-related allograft rejection is lacking. Here we found that second hand smoke (SHS) hindered long-term islet allograft survival induced by CD154 costimulatory blockade plus donor-specific splenocyte transfusion (DST), although it failed to alter acute islet allograft rejection. SHS did not directly interfere with vigorously alloreactive T-cell proliferation in vivo and in vitro. Neither naturally occurring nor induced CD4+CD25+ Treg cell numbers were significantly reduced by SHS. However, SHS suppressed mRNA and protein expression of indoleamine 2, 3-dioxygenase (IDO) and its activity upon transplantation while IDO overexpression in islet allografts restored their long-term survival induced by CD154 blockade. Therefore, SHS prevents long-term allograft survival by inhibiting IDO expression and activity. Thus, our study for the first time demonstrates that SHS shortens allograft survival in a cause-effect manner and unveils a novel immunologic mechanism underlying smoking-related allograft rejection.
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