Lysosomal localization of murine CD1d mediated by AP-3 is necessary for NK T cell development.
The presentation of lipid and glycolipid Ags to T cells is mediated through CD1 molecules. In the mouse and rat only a single isoform, CD1d, performs these functions, while humans and all other mammals studied have members of both group I (CD1a, -b, and -c) and group II (CD1d) isoforms. Murine CD1d contains a cytoplasmic tyrosine-based sorting motif that is similar to motifs recognized by adaptor protein complexes that sort transmembrane proteins. Here we show that the adaptor protein complex, AP-3, directly interacts with murine CD1d and controls its targeting to lysosomes. AP-3 deficiency results in a redistribution of CD1d from lysosomes to the cell surface of thymocytes, B cell-depleted splenocytes, and dendritic cells. The altered trafficking of CD1d in AP-3-deficient mice results in a significant reduction of NK1.1(+)TCR-beta(+) and CD1d tetramer-positive cells, consistent with a defect in CD1d self-Ag presentation and thymocyte-positive selection. The AP-3 complex has recently been shown to associate with the human CD1b isoform, which has an intracellular distribution pattern similar to that of murine CD1d. We propose that lysosomal sampling may be so critical for efficient host defense that mice have evolved mechanisms to target their single CD1 isoform to lysosomes for sampling lipid Ags. Here we show the dominant mechanism for this trafficking is mediated by AP-3.
Cernadas
Manuela
M
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Sugita
Masahiko
M
van der Wel
Nicole
N
Cao
Xiaochun
X
Gumperz
Jenny E
JE
Maltsev
Sergei
S
Besra
Gurdyal S
GS
Behar
Samuel M
SM
Peters
Peter J
PJ
Brenner
Michael B
MB
D033963:Adaptor Protein Complex 3; D000818:Animals; D018949:Antigens, CD1 / Q000096:biosynthesis / Q000378:metabolism*; D055610:Antigens, CD1d; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018655:Lymphocyte Count; D008247:Lysosomes / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021122:Protein Subunits / Q000378:metabolism / Q000502:physiology; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection
D033963:Adaptor Protein Complex 3; D018949:Antigens, CD1; D055610:Antigens, CD1d; C526877:CD1D protein, human; D004268:DNA-Binding Proteins; D021122:Protein Subunits; D014157:Transcription Factors