AbstractT cell clones and subsequently hybridomas were generated from rabies virus‐immune C3H/He mice to an immunodominant epitope of the viral nucleoprotein, termed 31D, that had previously been identified by a 15‐amino acid‐long synthetic peptide. T cells to this epitope that by phenotypical and functional characteristics belonged to the T helper cell subset were shown to respond to most rabies and rabies‐related viruses. In order to define the minimal sequence needed to elicit a response from 31D‐specific T cell clones or hybridomas, a number of peptides of varied lengths,i.e.3–32 amino acids long, were tested. The ability of the peptides to induce a response was inversely correlated in their lengths,i.e., short peptides (3–5 amino acids long) had to be used at 106times higher concentrations as compared to long peptides (15 or 32 amino acids long). Conversely, the specificity of the T cell response was directly correlated to the length of the peptides,i.e., while the response to 15‐amino acid‐long peptides exhibited a high degree of specificity, the response to 3‐ to 5‐amino acid‐long peptides showed a high degree of flexibility. The long as well as the short peptides had to be presented in association with I‐Ek. We speculate that in this system the T cell receptor interacts predominantly with a peptide‐induced modif