Natural CD8+CD122+ T Cells Are More Potent in Suppression of Allograft Rejection Than CD4+CD25+ Regulatory T Cells

Abstract

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.

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

“…Perhaps that is why we found that administration of IL-2 did not significantly promote CD8 1 CD122 1 Treg suppression of allograft rejection. 20 Instead, we demonstrated that administration of low doses of IL-15 promoted their homeostatic proliferation and enhanced their suppression of allograft rejection. 20 Taken together, both the B7/CD28 costimulatory and PD-L1/PD-1 coinhibitory pathways are required for optimal CD8 1 CD122 1 Treg-mediated suppression, while IL-15 boosts their suppressive capacity via promoting their proliferation or expansion.…”

“…20 Instead, we demonstrated that administration of low doses of IL-15 promoted their homeostatic proliferation and enhanced their suppression of allograft rejection. 20 Taken together, both the B7/CD28 costimulatory and PD-L1/PD-1 coinhibitory pathways are required for optimal CD8 1 CD122 1 Treg-mediated suppression, while IL-15 boosts their suppressive capacity via promoting their proliferation or expansion. However, it remains unknown whether CD8 1 CD122 1 Tregs can modulate antigen-presenting cells, which in turn, regulate aggressive effector CD4 1 or CD8 1 T cells.…”

“…We found that CD8 1 CD122 1 Tregs were much more effective in the suppression of allograft rejection and underwent faster homeostatic proliferation than CD4 1 CD251 Tregs. 20 Moreover, they produced more IL-10 and were more potent in the suppression of in vitro T-cell proliferation than CD4 1 CD25 1 Tregs. Most importantly, transfer of CD8 1 CD122 1 , but not CD4 1 CD25 1 , Tregs, together with administration of recombinant IL-15, significantly prolonged allograft survival in immunocompetent, wild-type mice.…”

“…Importantly, we have recently shown that CD8 1 CD122 1 Tregs are more potent in the suppression of allograft rejection than conventional CD4 1 CD25 1 Tregs. 20 Therefore, it is imperative to conduct more studies to lay the groundwork for clinical trials using CD8 1 CD122 1 Tregs in the future.…”

Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation

“…Maternal CD8 + T cell responses can also affect placental function (40)(41)(42). Recent studies in mouse models have indicated that the presence of the naturally occurring CD8 + T cell subset CD8 + CD122 + T cells is capable of suppressing inflammation in autoimmunity, transplantation, and other inflammatory conditions (43)(44)(45). However, to date, the mediators involved in the generation of CD8 + CD122 + T cells and their functional role in pregnancy maintenance remain unknown.…”