CTLA-4 blockade abrogates protection by regulatory T cells in ...

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) expressed at high levels by CD4(+)CD25(+)CD45RB(low) regulatory T cells (Treg) is essential to their homeostatic and immunoregulatory functions. However, its relevance to anti-inflammatory roles of Treg in the context of colitogenic innate immune response during pathogenic bacterial infections has not been examined. We showed earlier in Rag2-deficient 129/SvEv mice that Treg cells are capable of suppressing colitis and colon cancer triggered by Helicobacter hepaticus, a wide-spread murine enterohepatic pathogen. Using this model, we now examined the effects of antibody blockade of CTLA-4 on Treg function during innate immune inflammatory response. Consistent with our previous findings, we found that a single adoptive transfer of Treg cells prior to infection prevented colitis development despite persistent H. hepaticus infection in recipient mice. However, when infected mice were injected with anti-CTLA-4 antibody along with Treg cell transfer, they developed a severe acute colitis with poor body condition that was not observed in Rag2-/- mice without Treg cell transfer. Despite high numbers of Foxp3(+) Treg cells, evident by immunohistochemical analyses in situ, the CTLA-4 antibody treated mice had severely inflamed colonic mucosa and increased rather than decreased expression levels of cytokines IFN-gamma and IL-2. These findings indicate that antibody blockade of CTLA-4 clearly abrogates Treg cell ability to suppress innate immune-driven colitis and suggest that Treg cell CTLA-4 cognate interactions may be necessary to maintain homeostasis among cells of innate immunity.