CD4(+)CD25(+ )T regulatory cells from FIV(+ )cats induce a unique anergic profile in CD8(+ )lymphocyte targets

BACKGROUND: Using the FIV model, we reported previously that CD4(+)CD25(+ )T regulatory (Treg) cells from FIV(+ )cats are constitutively activated and suppress CD4(+)CD25(- )and CD8(+ )T cell immune responses. In an effort to further explore Treg-mediated suppression, we asked whether Treg cells induce anergy through the alteration of production of cyclins, cyclin-dependent kinases and their inhibitors. RESULTS: Lymphocytes were obtained from control or FIV(+ )cats and sorted by FACS into CD4(+)CD25(+ )and CD8(+ )populations. Following co-culture with CD4(+)CD25(+ )cells, CD8(+ )targets were examined by Western blot for changes in cyclins D(3), E and A, retinoblastoma (Rb) protein, as well as the cyclin dependent kinase inhibitor p21(cip1). Following co-culture with CD4(+)CD25(+)cells, we observed up-regulation of p21(cip1 )and cyclin E, with down-regulation of cyclin D(3), in CD8(+ )cells from FIV(+ )cats. As expected, CD8(+ )targets from control cats were quiescent with little up-regulation of p21(cip1 )and cyclin E. There was also a lack of Rb phosphorylation in CD8(+ )targets consistent with late G(1 )cell cycle arrest. Further, IL-2 mRNA was down regulated in CD8(+ )cells after co-culture with CD4(+)CD25(+ )Treg cells. Following CD4(+)CD25(+ )co-culture, CD8(+ )targets from FIV(+ )cats also had increased Foxp3 mRNA expression; however, these CD8(+)Foxp3(+ )cells did not exhibit suppressor function. CONCLUSIONS: Collectively, these data suggest that CD4(+)CD25(+ )Treg cells from FIV(+ )cats induce CD8(+ )anergy by disruption of normal G(1 )to S cell cycle progression.