AMINO-ACID-RESIDUES THAT FLANK CORE PEPTIDE EPITOPES AND THE EXTRACELLULAR DOMAINS OF CD4 MODULATE DIFFERENTIAL SIGNALING THROUGH THE T-CELL RECEPTOR

Hen egg lysozyme 52-61-specific CD4(+) T cells responded by interleuki n 2 (IL-2) secretion to any peptide containing this epitope regardless of length of NH2- and COOH-terminal composition. However, CD4(-) vari ants could only respond to peptides containing the two COOH-terminal t ryptophans at positions 62 and 63. Substitutions at these positions de fined patterns of reactivity that were specific for individual T cells inferring a T cell receptor (TCR)-based phenomenon. Thus, the fine sp ecificity of major histocompatibility complex (MHC)-peptide recognitio n by the TCR was dramatically affected by CD4 and the COOH-terminal pe ptide composition. Peptides that failed to induce IL-2 secretion in th e CD4(-) variants nevertheless induced strong tyrosine phosphorylation of CD3 zeta. Thus, whereas the TCR still recognized and bound to the MHC class II-peptide complex resulting in protein phosphorylation, thi s interaction failed to induce effective signal transduction manifeste d by IL-2 secretion. This provides a clear example of differential sig naling mediated by peptides known to be naturally processed. In additi on, the external domains of CD4, rather than its cytoplasmic tail, wer e critical in aiding TCR recognition of all peptides derived from a si ngle epitope. These data suggest that the nested flanking residues, wh ich are present on MHC class II but not class I bound peptides, are fu nctionally relevant.