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TAP-Independent MHC Class I Peptide Antigen Presentation to Alloreactive CTL Is Enhanced by Target Cell Incubation at Subphysiologic Temperatures¹

Yan Shi^2,*,, Kelly D. Smith^3,*, and Charles T. Lutz^4,*,,§

Departments of ^* Pathology and Microbiology and Graduate Program in Immunology and ^§ Molecular Biology, University of Iowa, Iowa City, IA 52242

We investigated the peptide dependency of a group of CD8⁺ anti-HLA-B7 alloreactive CTL. The CTL killed target cells after acid denaturation of more than 98% of target cell surface peptide/MHC class I complexes. The CTL also killed TAP^- HLA-B7-transfected T2 (T2B7) cells. The killing was enhanced by target cell incubation at 26°C. Despite these findings, which suggested peptide-independent allorecognition, CTL-mediated cytolysis was reduced or abolished by several point mutations affecting the HLA-B7 peptide-binding groove. Acid denaturation of HLA complexes on T2B7 cells prohibited CTL recognition. CTL recognition was restored by T2B7 cell incubation with ß₂-microglobulin and a single HPLC fraction containing peptides extracted from TAP⁺HLA-B7⁺ cells, but not by any of a panel of 17 synthetic HLA-B7-binding peptides. These findings indicated that CTL allorecognition was peptide specific. Sensitizing peptide was extracted from T2B7 cells only after incubation at 26°C. The amount of peptide detected in TAP⁺ cells was at least 10-fold and 100-fold greater than that detected in TAP^- cells incubated at 26°C and at 37°C, respectively. TAP-independent peptide epitope presentation was sensitive to treatment with brefeldin A, but not sensitive to treatment with chloroquine, consistent with an endogenous peptide source. We propose that subphysiologic temperature incubation can enhance peptide/MHC class I presentation in the total absence of TAP function.

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