| Full in vivo activation of naive T lymphocytes by cognate antigen requires antigen recognition and CD28 costimulation in an inflammatory environment. If antigenic stimulation of CD4+ T cells occurs in a non-inflammatory environment, the reactive CD4+ T cells develop T cell anergy or regulatory functions (iTregs) capable of suppressing autoimmune development. It is possible that T cell suppression may also inhibit anti-tumor immune responses and immunotherapy. The therapeutic infusion of tumor-specific T lymphocytes aims to achieve tumor eradication by circumventing obstacles to naive T cell priming and expansion in the tumor-bearing host. However, this also requires the ex vivo expanded T cells to function unimpeded following their infusion. The effect of antigen-induced regulatory development on anti-tumor immunotherapy, and the mechanisms controlling their functional development, remain largely unknown, and are the focus of my investigation.;I developed a system to study the function of naive CD4+ T cell activation, in the context of either non-inflammatory antigen presentation and/or a lack of CD28 costimulation, to analyze the host response to tumor specific adoptive therapy and active immunization. I furthermore characterized the in vivo generation of antigen-induced CD4+ T cells with regulatory capacity to determine their mechanism of development.;Here I show that naive CD4+CD25- T cells deprived of either LPS-induced or CD28-mediated costimulation develop regulatory activity upon primary in vivo antigenic stimulation. The regulatory activity of these cells is capable of precluding tumor eradication by adoptive therapy and in vivo priming of antigen specific CD4+ T cells. I show that CD28 engagement enhances immunity by decreasing Foxp3 expression levels, a critical determinant of regulatory T cell activity and development. My findings demonstrate that CD28 engagement is insufficient to prevent suppression from prevailing, but is critical to promote immunity by preempting regulatory T cell dominance. These results imply that anti-tumor adoptive T cell therapy as well as active immunization strategies must overcome both pre-existing and induced in the course of therapy regulatory T cell development to succeed. I thus demonstrate a novel function of CD28, which is to promote immunity in trans by preempting the in vivo dominance of T cell regulatory activity. |
