Loading of peptides onto major histocompatibility complex class I molecules involves a multifactorial complex that includes tapasin (TPN), a membrane protein that tethers empty class I glycoproteins to the transporter associated with antigen processing. To evaluate the in vivo role of TPN, we have generated Tpn mutant mice. In these animals, most class I molecules exit the endoplasmic reticulum (ER) in the absence of stably bound peptides. Consequently, mutant animals have defects in class I cell surface expression, antigen presentation, CD8+ T cell development, and immune responses. These findings reveal a critical role of TPN for ER retention of empty class I molecules. Tpn mutant animals should prove useful for studies on alternative antigen-processing pathways that involve post-ER peptide loading.
Bibliographical noteFunding Information:
The authors thank M. Bevan, M. Boothby, B. Hogan, J. Monaco, H. Ploegh, A. Porgador, N. Shastri, P. Soriano, and R. M. Welsh for providing various reagents, A. Davis, D. McFarland, and J. Wei for technical assistance, and S. Joyce for helpful comments on the manuscript. This work was supported by the Howard Hughes Medical Institute (to L. V. K.), the Leukemia and Lymphoma Society (to L. C. E.), American Cancer Society grant RPG-98-036-01-CIM (to L. C. E.), and NIH grants AI39501 (to L. C. E.), AI30581 (to T. S.), and AI46455 (to R. R. B.). T. N. G. is the recipient of a Cancer Research Institute/CIGNA Foundation Fellowship.
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