Abstract
Mounting evidence has shown that naturally occurring CD8+CD122+ T cells are regulatory T cells (Tregs) that suppress both autoimmunity and alloimmunity. We have previously shown that CD8+CD122+PD-1+ Tregs not only suppress allograft rejection, but also are more potent in suppression than conventional CD4+CD25+ Tregs. However, the mechanisms underlying their suppression of alloimmunity are not well understood. In an adoptive T-cell transfer model of mice lacking lymphocytes, we found that suppression of skin allograft rejection by CD8+CD122+PD-1+ Tregs was mostly dependent on their expression of Fas ligand as either lacking Fas ligand or blocking it with antibodies largely abolished their suppression of allograft rejection mediated by transferred T cells. Their suppression was also mostly reversed when effector T cells lacked Fas receptor. Indeed, these FasL+ Tregs induced T cell apoptosis in vitro in a Fas/FasL-dependent manner. However, their suppression of T cell proliferation in vitro was dependent on IL-10, but not FasL expression. Furthermore, adoptive transfer of CD8+CD122+PD-1+ Tregs significantly extended allograft survival even in wild-type mice if Tregs lacked Fas receptor or if recipients received recombinant IL-15, as these two measures synergistically expanded adoptively-transferred Tregs in recipients. Thus, this study may have important implications for Treg therapies in clinical transplantation.
Highlights
CD4+CD25+ regulatory T cells (Treg) prevent allograft rejection and are essential for tolerance in animal models [1,2,3,4,5,6,7,8]
In an adoptive T-cell transfer model of Rag1-/- mice, we found that suppression of skin allograft rejection in by CD8+CD122+PD-1+ Tregs was mostly dependent on their expression of Fas ligand
To search for the mechanisms underlying immunosuppression mediated by memory-like CD8+CD122+PD-1+ Tregs, we determined a role for Fas ligand (FasL) in their suppression of allograft rejection
Summary
CD4+CD25+ regulatory T cells (Treg) prevent allograft rejection and are essential for tolerance in animal models [1,2,3,4,5,6,7,8]. Mounting evidence has demonstrated that naturally occurring CD8+CD122+ T cells are Tregs that inhibit conventional T cell responses [9,10,11,12,13,14], antitumor immunity [15], as well as autoimmunity [16, 17]. CD8+CD122+ Tregs likely correspond to their CD4+CD25+ counterparts since CD122 is the β subunit of IL-2 receptor on T cells while CD25 is the α subunit of the same receptor [21]. CD8+CD122+PD-1+ Tregs likely correspond to their CD4+CD25+FoxP3+ counterparts, and they probably cooperate to maintain www.impactjournals.com/oncotarget the immunologic homeostasis and keep autoimmune responses in check. It is imperative to fully understand the mechanisms responsible for the Treg suppression so that they can be fully exploited to inhibit allograft rejection in an immune competent recipient or even in humans
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