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Impact of Antigen Presentation on TCR Modulation and Cytokine Release: Implications for Detection and Sorting of Antigen-Specific CD8⁺ T Cells Using HLA-A2 Wild-Type or HLA-A2 Mutant Tetrameric Complexes¹

Elke Jäger^*, Russell Salter, Chiara Castelli, Hanni Höhn, Kirsten Freitag, Julia Karbach^*, Claudia Neukirch, Antje Necker^¶, Alexander Knuth^* and Markus J. Maeurer^2,

^* Medizinische Klinik II, Hämatologie-Onkologie, Krankenhaus Nordwest, Frankfurt, Germany; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; Istituto Tumori Milano, Milano, Italy; Department of Medical Microbiology, University of Mainz, Hochhaus Augustusplatz, Mainz, Germany; and ^¶ Immunomics Operations, Beckman Coulter, Marseille, France

Soluble MHC class I molecules loaded with antigenic peptides are available either to detect and to enumerate or, alternatively, to sort and expand MHC class I-restricted and peptide-reactive T cells. A defined number of MHC class I/peptide complexes can now be implemented to measure T cell responses induced upon Ag-specific stimulation, including CD3/CD8/-chain down-regulation, pattern, and quantity of cytokine secretion. As a paradigm, we analyzed the reactivity of a Melan-A/MART-1-specific and HLA-A2-restricted CD8⁺ T cell clone to either soluble or solid-phase presented peptides, including the naturally processed and presented Melan-A/MART-1 peptide AAGIGILTV or the peptide analog ELAGIGILTV presented either by the HLA-A2 wild-type (wt) or mutant (alaninevaline aa 245) MHC class I molecule, which reduces engagement of the CD8 molecule with the HLA-A2 heavy chain. Soluble MHC class I complexes were used as either monomeric or tetrameric complexes. Soluble monomeric MHC class I complexes, loaded with the Melan-A/MART-1 peptide, resulted in CD3/CD8 and TCR -chain down-regulation, but did not induce measurable cytokine release. In general, differences pertaining to CD3/CD8/-chain regulation and cytokine release, including IL-2, IFN-, and GM-CSF, were associated with 1) the format of Ag presentation (monomeric vs tetrameric MHC class I complexes), 2) wt vs mutant HLA-A2 molecules, and 3) the target Ag (wt vs analog peptide). These differences are to be considered if T cells are exposed to recombinant MHC class I Ags loaded with peptides implemented for detection, activation, or sorting of Ag-specific T cells.

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