Two human helper T cell determinants in influenza have been identified, one in the hemagglutinin and the other in the matrix protein (M1). Both were shown to be DR1 restricted by using transfected L cells to present antigen. Comparison of the sequences of the two peptides revealed a similar pattern that could account for their DR1 specificity if the peptides adopt a helical conformation. The model was supported by the demonstration that hybrid peptides, composed of the amino acids that interact with DR1 from one determinant and the residues that interact with the T cell receptor from the other, were recognized by each clone. The generality of the motif was confirmed by the finding that DR1 individuals respond to a ragweed peptide containing the defined pattern.