Mutation of a Positively Charged Cytoplasmic Motif within CD1d Results in Multiple Defects in Antigen Presentation to NKT Cells

Abstract

CD1d is an MHC class I-like molecule that presents glycolipid Ags to types I and II NKT cells. The YxxI motif in the cytoplasmic tail of CD1d contributes to its intracellular localization to the endolysosomal compartment and is important for Ag presentation to type I NKT cells. In this study, we identified the 327–329RRR motif in CD1d and showed that it is critical for the control of CD1d intracellular trafficking and Ag presentation. The replacement of the arginines in this motif with alanines resulted in the extensive accumulation of CD1d in lysosomes but did not affect the cell surface expression. The defect in its cellular localization was accompanied by defects in Ag presentation to both type I and type II NKT cells. These results demonstrated that the 327–329RRR motif of CD1d is required for proper cellular distribution of CD1d and optimal Ag presentation to both type I and type II NKT cells.

Type II natural killer T cells use features of both innate-like and conventional T cells to recognize sulfatide self antigens

“…The lack of antigenicity observed for lysolecithin (also known as lysophospatidylcholine) is likely the result of the drastically different polar moiety (a phosphorylcholine group) of this lipid compared to the other antigens carrying hexose sugars. Moreover, the differences in the antigen presentation between plate bound CD1d and antigen-presenting cells (APCs) suggests that APCs either process antigens into an inactive form or prevent their presentation at the cell surface, consistent with the reported requirement of mCD1d trafficking to the lysosomal compartment for type II NKT cell activation 22,34 .…”

The effect of intracellular trafficking of CD1d on the formation of TCR repertoire of NKT cells

“…Indeed, similar trafficking was observed when MHC-II or Ii was overexpressed with CD1d-TD (60,67). However, CD1d-RATD traffic to lamp-1 + compartment regardless of the existence of MHC-II or Ii (66). Moreover, CD1d-TD trafficked to lamp-1 + compartment by overexpressed MHC-II or Ii showed recovered antigen presentation to type I NKT cells compared to CD1d-TD (60,67).…”

“…Moreover, CD1d-TD trafficked to lamp-1 + compartment by overexpressed MHC-II or Ii showed recovered antigen presentation to type I NKT cells compared to CD1d-TD (60,67). However, the antigen presentation ability of CD1d-RATD to type I NKT cells was not recovered even though CD1d molecules were highly accumulated in lamp-1 + compartment (66).…”

“…Recently, it has been shown that when three consecutive arginines of this motif in murine CD1d were replaced with non-charged alanines (CD1d-RA), antigen presentation ability of CD1d-RA to type I NKT cells was severely reduced either for endogenous self lipid antigen and exogenous lipid antigens even though CD1d molecules were highly accumulated in the endolysosomal (lamp-1 + ) compartments. Moreover, CD1d-RA also had a defect in antigen presentation to type II NKT cells (66).…”

Type II NKT cells: a distinct CD1d-restricted immune regulatory NKT cell subset

“…The role of a major intracellular signaling molecule, PI3 kinase, was also established by employing the well-known inhibitor Wortmanin. In another study, the accumulation of CD1d in the lysosomal compartment owing to the lack of a triple arginine motif results in the inhibition of lipid presentation to both NKT cells without effecting cell surface CD1d expression (Shin et al 2012). In contrast, a truncated CD1d tail inhibits antigen presentation to type I but not type II NKTcells suggesting differential modes of cellular signaling for two subsets (Chiu et al 1999; Chiu et al 2002; Jayawardena-Wolf et al 2001).…”