Autophagy-mediated antigen presentation for CD1d-restricted NKT cell recognition
Final Report Abstract
Invariant NKT (iNKT) cells are innate-like T cells with powerful regulatory functions that recognize glycolipid antigens presented by the CD1d protein. CD1d molecules survey endocytic pathways to bind lipid antigens in MHC class II containing compartments (MIICs) before recycling to the plasma membrane. Autophagosomes intersect with MIICs and autophagy-related proteins are known to support antigen loading for increased CD4+ T cell immunity. Here, we report that CD1d partly colocalizes with LC3+ endosomal compartments in murine primary dendritic cells (DCs). Mice with DC-conditional deletion in the essential autophagy gene Atg5 showed better CD1d-restricted glycolipid presentation in vivo. These effects led to efficient activation of iNKT cells as measured by IFN-γ and IL-4 release upon antigen stimulation, and also to increased phenotypic DC maturation. Enhanced iNKT cell activation was independent of receptor-mediated glycolipid uptake or costimulatory signals. Instead, loss of Atg5 in DCs impaired CD1d internalization and increased surface expression of stimulatory CD1d:glycolipid complexes. These findings indicate that in DCs the autophagic process attenuates iNKT cell activation, in contrast with the supporting role in CD4+ T cell stimulation. I started a new project related to the initially funded project which addresses the role of autophagy-mediated antigen presentation in autoimmune CNS inflammation.
