Invariant natural killer T cells in autoimmune cholangiopathies: Mechanistic insights and therapeutic implications

Invariant natural killer T cells (iNKT cells) constitute a specialized subset of lymphocytes that bridges innate and adaptive immunity through a combination of traits characteristic of both conventional T cells and innate immune cells. iNKT cells are characterized by their invariant T cell receptors and discerning recognition of lipid antigens, which are presented by the non-classical MHC molecule, CD1d. Within the hepatic milieu, iNKT cells hold heightened prominence, contributing significantly to the orchestration of organ homeostasis. Their unique positioning to interact with diverse cellular entities, ranging from epithelial constituents like hepatocytes and cholangiocytes to immunocytes including Kupffer cells, B cells, T cells, and dendritic cells, imparts them with potent immunoregulatory abilities. Emergering knowledge of liver iNKT cells subsets enable to explore their therapeutic potential in autoimmne liver diseases. This comprehensive review navigates the landscape of iNKT cell investigations in immune-mediated cholangiopathies, with a particular focus on primary biliary cholangitis and primary sclerosing cholangitis, across murine models and human subjects to unravel the intricate involvements of iNKT cells in liver autoimmunity. Additionally, we also highlight the prospectives of iNKT cells as therapeutic targets in cholangiopathies. Modulation of the equilibrium between regulatory and proinflammatory iNKT subsets can be defining determinant in the dynamics of hepatic autoimmunity. This discernment not only enriches our foundational comprehension but also lays the groundwork for pioneering strategies to navigate the multifaceted landscape of liver autoimmunity.