Regulation of CD1 Function and NK1.1 + T Cell Selection and Maturation by Cathepsin S

NK1.1 + T cells develop and function through interactions with cell surface CD1 complexes. In I-A b mice lacking the invariant chain (Ii) processing enzyme, cathepsin S, NK1.1 + T cell selection and function are impaired. In vitro, thymic dendritic cells (DCs) from cathepsin S −/− mice exhibit defective presentation of the CD1-restricted antigen, α-galactosylceramide (α-GalCer). CD1 dysfunction is secondary to defective trafficking of CD1, which colocalizes with Ii fragments and accumulates within endocytic compartments of cathepsin S −/− DCs. I-A k , cathepsin S −/− mice do not accumulate class II-associated Ii fragments and accordingly do not display CD1 abnormalities. Thus, function of CD1 is critically linked to processing of Ii, revealing MHC class II haplotype and cathepsin S activity as regulators of NK T cells.