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A Novel Trafficking Signal within the HLA-C Cytoplasmic Tail Allows Regulated Expression upon Differentiation of Macrophages¹

Malinda R. Schaefer^*, Maya Williams, Deanna A. Kulpa, Pennelope K. Blakely, Anna Q. Yaffee^¶ and Kathleen L. Collins^2,*,,,

^* Graduate Program Immunology, Graduate Program in Cellular and Molecular Biology, Department of Medicine, Department of Microbiology and Immunology, and ^¶ Masters of Public Health Program, University of Michigan, Ann Arbor, MI 48109

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants RO1 AI051198 and AI046998. M.W. was supported by the University of Michigan Cellular and Molecular Biology Training Program. M.R.S. was supported by the University of Michigan Research Training in Experimental Immunology Training Grant and the Herman and Dorothy Miller Award. D.A.K. was supported by an Irvington Institute Fellowship.

² Address correspondence and reprint requests to Dr. Kathleen L. Collins, University of Michigan, 3510 Medical Science Research Building I, 1150 West Medical Center Drive, Ann Arbor, MI 48109. E-mail address: klcollin{at}umich.edu

³ Abbreviations used in this paper: MHC-I, MHC class I; KIR, killer cell Ig-like receptor; HA, hemagglutinin; ER, endoplasmic reticulum; MFI, mean fluorescence intensity; RIPA, radioimmunoprecipitation assay; endo H, endoglycosidase H; IRES, internal ribosome entry site.