Speaker: Ruka Setoguchi, Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Host: Ryo Morimoto, Department of Molecular Biology, MIMS
The mechanisms that regulate CD8 T cell responses and maintain memory CD8 T cell homeostasis remain incompletely understood. Previous observations that adoptively transferred memory CD8 T cells persist poorly in MHC class II (MHCII)-deficient mice suggested that CD4 T cell help is required for their maintenance. Here, we demonstrate that chronic interferon-γ (IFN-γ) signaling, rather than CD4 T cell deficiency, is responsible for the attrition of memory CD8 T cells in MHCII-deficient environments. Neutralization of IFN-γ restores memory CD8 T cell numbers in MHCII-deficient mice, whereas repeated IFN-γ administration or transduction with a gain-of-function STAT1 mutant reduces their numbers in wild-type mice.
We further show that excessive IFN-γ is produced predominantly by endogenous colonic CD8 T cells and promotes colonic inflammation in MHCII-deficient mice. Moreover, the combined absence of CD4 T cells and MHCII–LAG-3 interactions drives aberrant CD8 T cell activation and excessive IFN-γ production, primarily in the colon. These findings indicate that the loss of MHCII-dependent regulation leads to dysregulated CD8 T cell responses in the colon and secondary depletion of memory CD8 T cells, thereby revealing an unappreciated mechanism controlling CD8 T cell responses and memory CD8 T cell homeostasis.
Speaker: Shohei Hori, Tokyo University, Japan
Host: Ryo Morimoto, Department of Molecular Biology, MIMS
Regulatory T (Treg) cells are central guardians of immune tolerance and tissue homeostasis. This notion is firmly supported by the finding that defective Treg development and function, caused by mutations in the Foxp3 gene, lead to devastating autoimmune diseases in both mice and humans. However, the molecular mechanisms that establish the epigenetic, transcriptional, and functional identity of Treg cells remain incompletely understood. Although Foxp3 has long been regarded as the master transcription factor of Treg cells, earlier studies suggested that its role in shaping their heterogeneous epigenetic and transcriptional landscapes might be limited or indirect. Our recent findings challenge this view. Using complementary gain- and loss-of-function approaches, we demonstrate that Foxp3 plays a more fundamental and direct role than previously appreciated, integrating cell-intrinsic states and environmental contexts to drive epigenetic and transcriptional programs that define Treg cell identity and function. Acting as a master yet context-dependent regulator, Foxp3 cooperates with signal-dependent transcription factors, including BATF, to coordinate the epigenetic and transcriptional programs underlying Treg cell identity and function.
Integrated Biomedical Science Seminars is a broad, open seminar series within life science.