Amino acid residues that flank core peptide epitopes and the extracellular domains of CD4 modulate differential signaling through the T cell receptor.

Abstract

StlmmaryHen egg lysozyme 52-61-specific CD4 + T cells responded by interleukin 2 (IL-2) secretion to any peptide containing this epitope regardless of length of NH2-and COOH-terminal composition. However, CD4-variants could only respond to peptides containing the two COOHterminal tryptophans at positions 62 and 63. Substitutions at these positions defined patterns of reactivity that were specific for individual T cells inferring a T cell receptor (TCR)-based phenomenon. Thus, the fine specificity of major histocompatibility complex (MHC)-peptide recognition by the TCR was dramatically affected by CD4 and the COOH-terminal peptide composition. Peptides that failed to induce IL-2 secretion in the CD4-variants nevertheless induced strong tyrosine phosphorylation of CD3~'. Thus, whereas the TCR still recognized and bound to the MHC class II-peptide complex resulting in protein phosphorylation, this interaction failed to induce effective signal transduction manifested by IL-2 secretion. This provides a dear example of differential signaling mediated by peptides known to be naturally processed. In addition, the external domains of CD4, rather than its cytoplasmic tail, were critical in aiding TCK recognition of all peptides derived from a single epitope. These data suggest that the nested flanking residues, which are present on MHC class II but not class I bound peptides, are functionally relevant.

Regulatory T Cells Inhibit Dendritic Cells by Lymphocyte Activation Gene-3 Engagement of MHC Class II

“…LAG-3 expressing T cell hybridomas were transduced as described (30) using the CD4 Ϫ variant T hybrid (3A9.N49; H-2A k -restricted, hen egg lysozyme (48 -63-specific) (31). LAG-3 expression was uniformly high in all transductants.…”

Flexibility in MHC and TCR Recognition: Degenerate Specificity at the T Cell Level in the Recognition of Promiscuous Th Epitopes Exhibiting No Primary Sequence Homology

“…Assays were performed essentially as previously described by Vignali and Strominger with slight modifications (28). In all assays B lymphoma cells (A-20) were used as APCs and labeled with a given peptide overnight before each assay.…”

The CD4+ T‐cell epitope‐binding register is a critical parameter when generating functional HLA‐DR tetramers with promiscuous peptides

“…It has been shown that residues flanking the core peptide might be involved in the interaction between the TCR and the MHC class II-peptide complex [36,52]. However, we could show that the HLA-DR Ã 1101 tetramers loaded with the anchor-tailored analogues enriched a population of specific T cells able to recognize also the WT peptide and displaying a rather clonally heterogeneous T-cell repertoire.…”