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Elucidation and Role of Critical Residues of Immunodominant Peptide Associated with T Cell-Mediated Parasitic Disease¹

Department of Pathology, Tufts University School of Medicine, Boston, MA 02111

Granulomatous inflammation in schistosomiasis is strictly dependent on CD4⁺ Th lymphocytes sensitized to egg Ags, but its intensity is genetically regulated. C3H and CBA (H-2^k) are strains of mice that develop large granulomas; they also strongly respond to the major egg Ag Sm-p40. We now show that the immunodominant epitope recognized by CD4⁺ Th cells from infected H-2^k mice is confined to 13-mer peptide 234–246 (PKSDNQIKAVPAS), which elicits an I-A^k-restricted Th1-type response. Using a panel of alanine-monosubstituted peptides, we identified Asp²³⁷ as the main contact residue with I-A^k. On the other hand, three TCR contact residues were essential to stimulate epitope-specific T cell hybridomas: for two hybridomas these were Asn²³⁸, Gln²³⁹, and Lys²⁴¹; and for one, Asn²³⁸, Lys²⁴¹, and Pro²⁴⁴. In one instance, alanine substitution for Gln²³⁹ generated an antagonist that blocked subsequent stimulation with wild-type peptide. Most importantly, replacement of Asn²³⁸, Gln²³⁹, or Lys²⁴¹ caused a profound loss of polyclonal CD4⁺ T cell reactivity from schistosome-infected mice. This study identifies the critical residues of immunodominant peptide 234–246 involved in the T cell response against the Sm-p40 egg Ag and suggests that suitable altered peptides may be capable of precipitating its down-regulation.

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