A novel trafficking signal within the HLA-C cytoplasmic tail allows regulated expression upon differentiation of macrophages.
MHC class I molecules (MHC-I) present peptides to CTLs. In addition, HLA-C allotypes are recognized by killer cell Ig-like receptors (KIR) found on NK cells and effector CTLs. Compared with other classical MHC-I allotypes, HLA-C has low cell surface expression and an altered intracellular trafficking pattern. We present evidence that this results from effects of both the extracellular domain and the cytoplasmic tail. Notably, we demonstrate that the cytoplasmic tail contains a dihydrophobic (LI) internalization and lysosomal targeting signal that is partially attenuated by an aspartic acid residue (DXSLI). In addition, we provide evidence that this signal is specifically inhibited by hypophosphorylation of the adjacent serine residue upon macrophage differentiation and that this allows high HLA-C expression in this cell type. We propose that tightly regulated HLA-C surface expression facilitates immune surveillance and allows HLA-C to serve a specialized role in macrophages.
Schaefer
Malinda R
MR
Graduate Program Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
Williams
Maya
M
Kulpa
Deanna A
DA
Blakely
Pennelope K
PK
Yaffee
Anna Q
AQ
Collins
Kathleen L
KL
D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D045142:Cross-Priming / Q000276:immunology; D003593:Cytoplasm / Q000276:immunology* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D015236:HLA-C Antigens / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008247:Lysosomes / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D020298:U937 Cells
D015236:HLA-C Antigens