기초과학연구소 초청세미나 (Yale University School of Medicine, 채욱진박사)
생명과학과
2011-12-05
세미나 장소 : 미정
세미나 일시 : 2011.12.19. (16:30)
세미나 발표자 : Yale University School of Medicine, 채욱진박사
세미나 일시 : 2011.12.19. (16:30)
세미나 발표자 : Yale University School of Medicine, 채욱진박사
The linkage between autoimmunity and cancer via adenomatous polyposis coli
IL-17A has been known to play an important role in autoimmunity. Yet the role of IL-17A and its isoform IL-17F in colorectal cancer has not been investigated. The deficiency of IL-17A and IL-17F in murine colorectal cancer model of Apc/Min+ mice significantly reduced intestinal tumorigenesis. Interestingly, regulatory T cells bearing this germline mutation of Apc (adenomatous polyposis coli) gene could not effectively regress intestinal tumorigenesis while adoptive transfer of wildtype regulatory T cell into Apc/Min+ mice effectively inhibited tumor growth. This suggests that the paradoxical role of Treg cells in colon cancer is indeed critically affected by Apc/Min+ mutation. Importantly, Apc/Min+ Tregs showed the decrease of GATA-3 while they are expanded substantially in the lamina propria, a transcriptional factor that is required to maintain Treg function in addition to Foxp3 in vivo. These lamina propria Tregs expressed mostly Helios, suggesting that the expansion of dysfunctional Treg population is mainly contributed by thymic derived Tregs. Further examination of inducible Treg differentiation showed that Apc/Min+ mutation directs preferential induction of Foxp3+ Tregs, but these Foxp3+ iTregs were dysfunctional to regress intestinal tumorigenesis. We further demonstrated that activation of Wnt pathway and IL-17A-mediated pathway impairs Apc/Min+ Treg function at the early phase of intestinal tumorigenesis to prevent inflammation, and thus favors intestinal tumorigenesis. More interestingly, regulatory T cells from Apc/Min+ mice were not able to prevent inflammatory bowel disease. The adoptive transfer of wildtype Treg induced a potent Wnt antagonist, Dikkopf-1, suggesting that wildtpe Treg can antagonize aberrant Wnt pathway in intestinal inflammation. Indeed, wildtype Tregs had high level of Dkk-1 expression. Further analysis showed that Dkk-1 is a potent regulator of regulatory T cell and CD4 T cell homeostasis. Taken together, our results suggest that IL-17A and Wnt signaling are two key components of regulating CD4 T cell homeostasis.