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J. Biol. Chem., Vol. 279, Issue 51, 53062-53070, December 17, 2004

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Misfolding of Major Histocompatibility Complex Class I Molecules in Activated T Cells Allows cis-Interactions with Receptors and Signaling Molecules and Is Associated with Tyrosine Phosphorylation^*

Susana G. Santos¶||, Simon J. Powis¶, and Fernando A. Arosa**

From the Division of Human Genetics and Genetic Disorders, Institute for Molecular and Cell Biology, 4150-180 Porto, Portugal, Molecular Immunology and Pathology, Instituto de Ciências Biomédicas Abel Salazar, 4099-003 Porto, Portugal, and ^¶Division of Cell Biology and Immunology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom

Knowledge of the origin and biochemical status of ₂-microglobulin-free or misfolded major histocompatibility complex (MHC)-I molecules is essential for understanding their pleiotropic properties. Here we show that in normal human T cells, misfolding of MHC-I molecules is turned on upon activation and cell division and is proportional to the level of proliferation. Immunoprecipitation showed that a number of proteins are associated with MHC-I heavy chains at the surface of activated T cells, including the CD8 receptor and the chaperone tandem calreticulin/ERp57, associations that rely upon the existence of a pool of HC-10-reactive molecules. Biochemical analysis showed that misfolded MHC-I molecules present at the cell surface are fully glycosylated mature molecules. Importantly, misfolded MHC-I molecules are tyrosine phosphorylated and are associated with kinase activity. In vitro kinase assays followed by reprecipitation indicated that tyrosine phosphorylation of the class I heavy chain is probably mediated by a Src tyrosine kinase because Lck was found associated with HC-10 immunocomplexes. Finally, we show that inhibition of tyrosine phosphorylation by using the Src-family tyrosine kinase inhibitor PP2 resulted in enhanced release of MHC-I heavy chains from the cell surface of activated T cells and a slight down-regulation of cell surface W6/32-reactive molecules. This study provides new insights into the biology of MHC-I molecules and suggests that tyrosine phosphorylation may be involved in the regulation of MHC-I misfolding and expression.

Received for publication, August 2, 2004 , and in revised form, October 5, 2004.

^* This work was funded in part by Fundação para a Ciência e a Tecnologia Grant POCTI/38264/MGI/2001. 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.

^|| This work is part of a Ph.D. thesis. Recipient of a PRAXIS XXI fellowship (SFRH/BD/2742/2000) from Fundação para a Ciência e a Tecnologia.

^** To whom correspondence should be addressed: Institute for Molecular and Cell Biology, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal. Tel.: 351-226074900; Fax: 51-226092404; E-mail: farosa{at}ibmc.up.pt.

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