The role of IFN-gamma in Th1 cell commitment

Once the immune system recognizes antigens, the naive CD4+ T cells can be activated and differentiate into two subsets of mature effector cells: type 1 T helper cells (Th1) producing IFN-gamma and type 2 T helper cells (Th2) secreting IL-4. Generally, IL-12 directs naive CD4+ T cells differentiation into Th1 cells and causes Th1 immune responses while IL-4 arouses Th2 cell differentiation and Th2 immune responses. Well-differentiated Th1 cells commit to produce IFN-gamma and irreversibly shut down the IL-4 expression. So far, the molecular basis of Th1 cell commitment is largely unknown. The goal of this dissertation is to explore the possible molecular mechanisms that lead to Th1 cell commitment.; Our lab previously reported that IFN-gamma stabilized Th1 cell phenotype. However, the exact mechanism by which IFN-gamma mediates Th1 commitment remains unknown. In my dissertation, I delineated two features of IFN-gamma effect on Th1 cell differentiation and commitment. First, I found that IFN-gamma inhibited STAT6 signaling through a novel mechanism in committed Th1 cells. IFN-gamma inhibited STAT6 phosphorylation at the initial stage but did not target on Jak1, 3, and IL-4 receptor. Neither did it act through SOCS1, SOCS3, SOCS5 or SHP-1. IFN-gamma suppressed STAT6 phosphorylation by inhibiting its recruitment to the IL-4 receptor. It might do so by inducing a STAT6-binding protein with 75 KDa molecular weight. Second, I demonstrated that IFN-gamma but not IL-12 was critical for silencing the IL-4-producing potential in Th1 cells. I found that IFN-gamma alone was able to promote Th1 cell differentiation and to silence the IL-4-producing potential in Th1 cells. STAT1 signaling instead of STAT4 signaling was essential for Th1 cell commitment. And T-bet was required for IFN-gamma-mediated Th1 cell commitment. To achieve this aim, STAT1 signaling not only inhibited STAT6 phosphorylation but also suppressed the occurrence of dimethyl-histone H3 lysine 4 in the Il4 gene locus in Th1 cells, a positive marker of open chromatin structure. Taken together, these findings support my dissertation hypothesis that IFN-gamma mediates Th1 cell commitment by inhibiting the STAT6 signaling and rendering the Il4 gene locus inaccessible.