The Ufmylation E3 Ligase, UFL1, is Essential for the Development and Functions of Invariant NKT Cells 2260769

Abstract

Abstract Introduction Invariant natural killer T (iNKT) cells originate from a common lineage with conventional T cells but diverge to become distinct lymphocytes that specifically recognize glycolipid antigens and exert rapid effector functions upon activation. iNKT cells display superior tumor infiltration compared to conventional T cells and can reprogram suppressive immune cells into antitumor phenotypes, making them attractive candidates for immunotherapy. However, functional and numerical defects in iNKT cells have been reported in various human cancers and animal models. The mechanisms regulating iNKT cell development and function remain incompletely understood. UFL1, the E3 ligase of the novel ufmylation pathway, facilitates the transfer of ubiquitin-fold modifier 1 (UFM1) to target proteins, thereby modulating their functions. The role of UFL1 in iNKT cell development and function is currently unknown. Methods We used wild-type mice, mice lacking UFL1 in T cells, and Rag1-deficient mice in this study. Bone marrow chimeras, flow cytometry, and in vitro iNKT cell stimulation were used to assess iNKT cell development and proliferation. Cytokine assays and the B16F10 mouse melanoma model were employed to investigate iNKT cell functions. Results Mice lacking UFL1 in T cells exhibited decreased numbers of iNKT cells in the thymus, spleen, and liver. Furthermore, UFL1-deficient iNKT cells failed to attain full maturation. Bone marrow transplantation studies supported a cell-intrinsic role for UFL1 in regulating iNKT cell development. Functional analyses revealed that UFL1-sufficient iNKT cells produced significantly higher levels of IFN-γ and IL-4 than UFL1-deficient iNKT cells. In addition, UFL1 was required for iNKT cells to effectively inhibit melanoma metastasis to the lung. Conclusion Our findings identify a critical role for UFL1 in iNKT cell biology and provide new insights into how iNKT cells can be more effectively harnessed as frontline immune cells in combating cancer and infection. Funding Source NIH (NIAID) Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)