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T Cell Recognition of Distinct Peptide:I-A^u Conformers in Murine Experimental Autoimmune Encephalomyelitis ¹

Jason C. Huang^*, Mei Han^*, Alfredo Minguela^*,, Silvia Pastor^*, Ayub Qadri^2,* and E. Sally Ward^3,*

^* Center for Immunology and Cancer Immunobiology Center, University of Texas Southwestern Medical Center, Dallas, TX 75390; and Seccion de Inmunologia, Hospital Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain

We have used T cells bearing TCRs that are closely related in sequence as probes to detect conformational variants of peptide-MHC complexes in murine experimental autoimmune encephalomyelitis in H-2^u mice. The N-terminal epitope of myelin basic protein (MBP) is immunodominant in this model. Our studies have primarily focused on T cell recognition of a position 4 analog of this peptide (MBP1–9[4Y]) complexed with I-A^u. Using site-directed mutagenesis, we have mapped the functionally important complementarity determining region residues of the 1934.4 TCR V domain. One of the resulting mutants (Tyr⁹⁵ to alanine in CDR3, Y95A) has interesting properties: relative to the parent wild-type TCR, this mutant poorly recognizes Ag complexes generated by pulsing professional APCs (PL-8 cells) with MBP1–9[4Y] while retaining recognition of MBP1–9[4Y]-pulsed unconventional APCs or insect cell-expressed complexes of I-A^u containing tethered MBP1–9[4Y]. Insect cell expression of recombinant I-A^u with covalently tethered class II-associated invariant chain peptide or other peptides which bind relatively weakly, followed by proteolytic cleavage of the peptide linker and replacement by MBP1–9[4Y] in vitro, results in complexes that resemble peptide-pulsed PL-8 cells. Therefore, the distinct conformers can be produced in recombinant form. T cells that can distinguish these two conformers can also be generated by the immunization of H-2^u mice, indicating that differential recognition of the conformers is observed for responding T cells in vivo. These studies have relevance to understanding the molecular details of T cell recognition in murine experimental autoimmune encephalomyelitis. They are also of particular importance for the effective use of multimeric peptide-MHC complexes to characterize the properties of Ag-specific T cells.

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