Title: The class II MHC processing and presentation pathway in human CD4⁺ T cells
Description: Presentation of peptide antigen by major histocompatability complex (MHC) class II regulates CD4 + T cell activation and homeostasis. In the human system, CD4 + T cells can express MHC class II and function as antigen-presenting cells (APC). We initiated this study to better understand the regulation of MHC class II expression in CD4 + T cells. We assessed the proteolytic processing pathway that controls MHC class II maturation in CD4 + T cells. We found that, similar to B cells, CD4 + T cells utilize cathepsin S to degrade the MHC class II chaperone invariant chain (Ii), and thereby regulate surface expression of MHC class II. We further characterized the proteolytic repertoire of CD4 + T cells and determined that CD4 + T cells lack asparagine endopeptidase (AEP) expression and activity. Although AEP has been reported to play an important role in the initiation of Ii processing in human cells, this enzyme is dispensable in CD4 + T cells. Using a specific inhibitor of AEP in human B cell lines, we confirmed that AEP is not required for Ii processing. Furthermore, we determined that the initiation of Ii processing is a redundant event regulated by both tissue type and MHC haplotype.

Having determined that processing of MHC class II in CD4 + T cells is remarkably similar to that of other APC, we went on to analyze expression of MHC class II in CD4 + T cells ex vivo . The MHC class II variant HLA-DR has been shown to distinguish a functionally distinct population of CD4 + CD25 hi FoxP3 + Tregs. We used CD127 to further characterize the CD25 hi memory Treg population. In CD25 hi CD127 lo natural Tregs, HLA-DR expression correlated with commitment to the Treg lineage, lack of replicative capacity, telomere erosion, and cellular senescence. As Treg deficiencies associated with multiple sclerosis (MS), we assayed Tregs isolated from patients with MS. We determined that the CD127 lo HLA-DR + Treg subset exhibits functional defects in late suppression, but not in early suppression. Our findings indicate that antigen presentation by CD4 + T cell contributes to the maintenance of CD4 + T cell homeostasis.