Peptides of 23 residues or greater are required to stimulate a high affinity class II‐restricted T cell response

Abstract

Helper T cells recognize fragments of antigen bound to the class II molecules on the surface of antigen-presenting cells. Naturally processed antigenic fragments have been isolated from the class II molecules and shown to be heterogeneous in length, ranging from 13 to 25 residues, and to vary at both the N and C termini. A 15-residue peptide in an extended conformation is predicted to fit in an open peptide-binding cleft of the class II molecules. Thus, the longer peptides observed bound to class II presumably have regions which reside outside the cleft. It is not known if the additional length contributes significantly to T cell activation. We have carried out a systematic analysis of the antigenicity of peptides of increasing length beyond the minimally defined T cell antigenic peptide. Here we show that the full functional activities of peptides representing the major antigenic determinant of the protein antigen, cytochrome c, minimally require that the peptides be 23 amino acids long. The long peptides do not require processing and are presented by purified class II molecules incorporated into synthetic membranes, indicating that such peptides associate directly with class II and require no additional cellular machinery for presentation. We also show that a hybrid peptide, 51 residues in length, containing a 29-residue cytochrome c peptide and a "promiscuous" peptide of tetanus toxoid, is more antigenic than the 23-residue peptide alone and significantly, does not require processing. Thus, the additional peptide length, although not predicted to bind in the peptide-binding groove of the MHC class II molecule, has a significant impact on the ability of the peptides to stimulate T cell responses maximally.

Yersinia-hsp60-reactive T cells are efficiently stimulated by peptides of 12 and 13 amino acid residues in a MHC class II (I-Ab)-restricted manner

“…Hence, both HKY and Y-hsp60 peptides were processed by the typical exogenous pathway, and uptake of HKY by APC occurred by phagocytosis. In contrast to recent published data, we found that longer peptides do not necessarily stimulate T cells more efficiently than shorter ones [32]. The concentration required for half-maximal T cell proliferation of some clones was lower for short peptides, and suggests that shorter peptides induce stronger or comparable T cell responses than do longer ones.…”

Antigen Presentation to Celiac Lesion-Derived T Cells of a 33-Mer Gliadin Peptide Naturally Formed by Gastrointestinal Digestion

“…Increasing antigenicity as a function of peptide length has also been reported for a cytochrome c epitope (24). T cell recognition of this epitope was independent of processing, and the antigenicity was continuously improved by extension of the core peptide region.…”

Long Peptide Vaccination Can Lead to Lethality through CD4+ T Cell-Mediated Cytokine Storm

“…Because SPs are presented by specific MHC alleles, patients should be selected according to HLA haplotype for inclusion in clinical trials. Long peptides (LPs) (15-35 aa) bind more efficiently to MHC II molecules for induction of optimal T cell responses (31,32). Long peptides may be preferentially presented by professional APCs, as, at least for MHC Irestricted epitopes, they require endocytosis and processing (33,34).…”