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J. Biol. Chem., Vol. 283, Issue 21, 14717-14727, May 23, 2008

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Major Histocompatibility Complex Class II-Peptide Complexes Internalize Using a Clathrin- and Dynamin-independent Endocytosis Pathway^*

Even Walseng¹, Oddmund Bakke^¶, and Paul A. Roche²

From the Experimental Immunology Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892, the Centre for Immune Regulation, Department of Molecular Biosciences, University of Oslo, Oslo 0316, Norway, and ^¶The Gade Institute, University of Bergen, Bergen 5021, Norway

Major histocompatibility complex (MHC) class II molecules (MHC-II) function by binding antigenic peptides and displaying these peptides on the surface of antigen presenting cells (APCs) for recognition by peptide-MHC-II (pMHC-II)-specific CD4 T cells. It is known that cell surface MHC-II can internalize, exchange antigenic peptides in endosomes, and rapidly recycle back to the plasma membrane; however, the molecular machinery and trafficking pathways utilized by internalizing/recycling MHC-II have not been identified. We now demonstrate that unlike newly synthesized invariant chain-associated MHC-II, mature cell surface pMHC-II complexes internalize following clathrin-, AP-2-, and dynamin-independent endocytosis pathways. Immunofluorescence microscopy of MHC-II expressing HeLa-CIITA cells, human B cells, and human DCs revealed that pMHC enters Arf6⁺Rab35⁺EHD1⁺ tubular endosomes following endocytosis. These data contrast the internalization pathways followed by newly synthesized and peptide-loaded MHC-II molecules and demonstrates that cell surface pMHC-II internalize and rapidly recycle from early endocytic compartments in tubular endosomes.

Received for publication, February 8, 2008 , and in revised form, March 20, 2008.

^* This work was authored, in whole or in part, by National Institutes of Health staff. This work was supported by the National Institutes of Health Intramural Program and the Norwegian Cancer Society (to O. B.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Videos 1-3.

¹ Supported by the Norwegian Research Council during most of this work.

² To whom correspondence should be addressed: Bldg. 10, Rm. 4B36, Bethesda, MD 20892. Tel.: 301-594-2595; Fax: 301-435-7923; E-mail: paul.roche{at}nih.gov.

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