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Differential Requirement for Tapasin in the Presentation of Leader- and Insulin-Derived Peptide Antigens to Qa-1^b-Restricted CTLs¹

LiQi Li^2,*, Barbara A. Sullivan^3,, Carla J. Aldrich, Mark J. Soloski, James Forman^¶, Andres G. Grandea, III^4,*, Peter E. Jensen and Luc Van Kaer^5,*

^* Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322; Department of Microbiology and Immunology, Indiana University School of Medicine, Evansville Center, Evansville, IN 47712; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; and ^¶ Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390

The loading of MHC class I molecules with peptides involves a variety of accessory proteins, including TAP-associated glycoprotein (tapasin), which tethers empty MHC class I molecules to the TAP peptide transporter. We have evaluated the role of tapasin for the assembly of peptides with the class Ib molecule Qa-1^b. In normal cells, Qa-1^b is predominantly bound by a peptide, the Qa-1 determinant modifier (Qdm), derived from the signal sequence of class Ia molecules. Our results show that tapasin links Qa-1^b to the TAP peptide transporter, and that tapasin facilitates the delivery of Qa-1^b molecules to the cell surface. Tapasin was also required for the presentation of endogenous Qdm peptides to Qdm-specific, Qa-1^b-restricted CTLs. In sharp contrast, tapasin expression was dispensable for the presentation of an insulin peptide to insulin-specific, Qa-1^b-restricted CTL isolated from TCR transgenic mice. However, tapasin deficiency significantly impaired the positive selection of these insulin-specific, Qa-1^b-restricted transgenic CD8⁺ T cells. These findings reveal that tapasin plays a differential role in the loading of Qdm and insulin peptides onto Qa-1^b molecules, and that tapasin is dispensable for retention of empty Qa-1^b molecules in the endoplasmic reticulum, and are consistent with the proposed peptide-editing function of tapasin.

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