GLI2 Regulates T Cell Proliferation in Cooperation with IL-2 Signaling 2309246

Abstract

Abstract Introduction GLI2, a transcription factor downstream of hedgehog (Hh) signaling, is essential in embryonic development. GLI2 is also known for regulating the proliferation of different cell types. Previous studies have shown that GLI2 plays a role in T helper 2 (Th2) polarization and asthma pathogenesis. However, its role in T cell homeostasis and proliferation remained poorly understood. Methods To investigate this, we used mice with conditional deletion of Gli2 in hematopoietic cells, Gli2fl/fl Vav_icre+/- (H-Gli2-/-) and Gli2fl/fl Vav_icre-/- (WT littermates). Results We observed a significantly increased frequency of CD4+ T cells and a corresponding reduction in CD8+ T cells in the spleen, lymph nodes, and peripheral blood of H-Gli2-/- mice compared to WT. However, this altered CD4/CD8 ratio persisted following immunization of mice with ovalbumin, indicating that immunization did not further modify the distribution of CD4+ and CD8+ cells. Additionally, T cells from H-Gli2-/- mice spleens exhibited markedly increased CD4+ and CD8+ T cell proliferation when stimulated in-vitro with anti-CD3 and anti-CD28. Importantly, supplementation with exogenous IL-2 enhanced the proliferation of T cells from WT, but not H-Gli2-/- mice, indicating that GLI2 restraints T cell proliferation through modulation of IL-2 or IL-2-dependent signaling or IL-2 enhances GLI2-mediated cell proliferation in WT cells. Ongoing studies using both H-Gli2-/- mice and mice expressing an active form of Gli2 (ΔN-Gli2+/-) models are focused on defining the molecular mechanism by which IL-2 modulates T cell proliferation in the presence of an intact GLI2, including its impact on IL-2 production, IL-2 receptor expression, and downstream STAT5 activation. Conclusion Together, these findings identify GLI2 as a critical regulator of T cell proliferation and may inform strategies to modulate immune responses in cancer and inflammatory diseases. Funding Source n/a Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)