GLI3 regulates T helper cell polarization in adult mice 2129

Description GLI3, a transcription factor downstream of hedgehog (Hh) signaling, is essential in embryonic development. GLI3 has also been suggested to play a role in immune cell function. We have shown GLI3 plays a role in TLR—induced inflammation in macrophages. However, its role in CD4+ T-helper cell inflammation has not been addressed. A recent study showed the Indian Hh promotes Th17 cell polarization, with GLI3 suggested as the mediator via CRISPR-mediated Gli3 knockout. While GLI3 modulates T cell development in embryonic mice, its role in adult hematopoiesis has not been investigated. We generated mice with conditional deletion of Gli3 in hematopoietic cells, Gli3fl/fl Vav_icre+/- (H-Gli3-/-) and Gli3fl/fl Vav_icre-/- (WT littermates). We found while Gli3 deficiency did not significantly affect overall T cell development in the thymus, it increased the number of DN2 cells in adult mice. This discrepancy was not due to changes in cell lineage commitment to γδ TCR, NK or NKT cells. Additionally, peripheral T cell populations and CD4+/CD8+ proliferation were similar in both genotypes. Moreover, polarizing naïve CD4+ T cells to Th cell subsets, revealed that in the absence of Gli3, the number of Th1 and Th17 cells producing IFN-γ and IL-17A respectively increased. This suggests GLI3 negatively modulates CD4+ T cell polarization toward Th1/Th17, suggesting its anti-inflammatory role in T cells. Further research is required to elucidate the signaling pathways involved. Funding Sources Funded by NIH COBRE Center of Integrated Biomedical and Bioengineering Research (CIBBR, P20 GM113131) Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)