Identifying novel regulatory pathways underlying T helper 1 cell immune responses

点击翻译按钮获取中文摘要

PROJECT SUMMARY During the course of an immune response, CD4+ T helper cells identify invading pathogens, proliferate, and  secrete cytokines to aid in immune-mediated clearance of infection. This results in an initial expansion of effector CD4+ T cells at the peak of infection. These include effector T helper 1 (TH1) cells, which mediate immune responses to intracellular pathogens. As pathogen is eliminated, the effector cell population is reduced, with the exception of a subset of long-lived memory T cells capable of responding more quickly and robustly to a repeated encounter with the pathogen. This effector-to-memory transition is required for the generation of both naturally occurring long-term and vaccine-induced immunity. In addition to their contribution to the memory cell pool, an emerging body of literature suggests that TH1 cells may also engage in aspects of humoral immunity via plasticity shared with the T follicular helper (TFH) cell subset. TFH cells engage in cognate interactions with B cells to assist in the production of pathogen-neutralizing antibodies. Taken together, the above findings suggest that TH1 cells are capable of undergoing stage-specific phenotypic changes that allow for contributions to humoral and memory cell immunity. Currently, however, gaps in knowledge exist regarding the molecular mechanisms by which these critical cellular transitions occur. Bcl-6 is a transcriptional repressor required for both TFH and central memory T (TCM) cell differentiation. Recently, we demonstrated that TH1 cells up-regulate Bcl-6-dependent TFH- and TCM-like profiles in response to diminished antigen stimulation and IL-2 signaling. Intriguingly, these cells also co-express IL-6Rα and IL-7R, cytokine receptors that support TFH and TCM differentiation, respectively (“IL-6Rα+IL-7R+ cells”). Importantly, our preliminary data indicate that subsequent exposure to IL-6 or IL-7 differentially regulates TFH and TCM genes in IL-6Rα+IL-7R+ cells. Therefore, we hypothesize that IL-6- and IL-7-dependent alterations to the transcriptional landscape of TH1-derived IL-6Rα+IL-7R+ cells allow them to contribute to humoral and memory cell responses. To test this hypothesis we will 1) determine the IL-6-dependent effects on phenotype and function of IL-6Rα+IL- 7R+ cells, 2) assess the IL-7-dependent effects on phenotype and function of IL-6Rα+IL-7R+ cells, and 3) assess the functional contribution of IL-6Rα+IL-7R+ cells to immune responses in vivo. The findings obtained from these studies will be significant, as they will provide novel insight into the molecular mechanisms that support previously unappreciated roles for TH1 cells in humoral and memory responses. In doing so, our work will provide the molecular building blocks for the design of novel immunotherapeutic strategies and increasingly effective vaccines.