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Novel Splicing of the Human MHC-Encoded Peptide Transporter Confers Unique Properties¹

Immunobiology Laboratory, Massachusetts General Hospital-East, Harvard Medical School, Charlestown, MA 02129

Presentation of intracellularly derived antigenic peptides to T cells requires their assembly together with MHC class I molecules in the endoplasmic reticulum (ER). Such peptides are delivered to the ER by an MHC-encoded transporter composed of TAP1 and TAP2 protein delivery. Here, the first alternative splicing of Tap2 is described. The human splice variant, termed Tap2iso, lacks exon 11 and original 3' untranslated region and contains a newly identified exon 12 and 3' untranslated region. The full-length Tap2iso cDNA (2496 bp) predicts a protein of 653 amino acids. Tap2iso mRNA was normally coexpressed with Tap2 mRNA in all human lymphocyte cell lines examined. Function of TAP2iso was evaluated at multilevel in TAP1/2iso and TAP1/2 cotransfected T2 cells, a mutant cell line deplete of endogenous Tap gene products. The TAP1-TAP2iso transporter facilitated the maturation of MHC class I molecules in the ER and restored surface expression of class I. Importantly, TAP1-TAP2iso transporters expressed in T2 cells exhibited distinct and opposing influences on peptide selectivities, at times exceeding 30-fold differences in competition experiments and attributable to diversity in the 3'-COOH tail. The common coexpression of an alternative splice product of the Tap2 gene may contribute to broaden immune diversity, a mechanism previously described to occur predominantly at the level of the TCR and MHC class I gene products.

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