Extension of a minimal T cell Determinant allows relaxation of the requirement for particular residues within the determinant

Abstract

The determinant recognized by a class II restricted helper T cell clone raised against a peptide corresponding to the C-terminal 24 residues of the heavy chain of influenza virus hemagglutinin (HA) was examined in detail. The sequence 309VKQNTLKL316 was identified as the minimal determinant for T cell activation but its stimulatory capacity was augmented by extension at either end. Sets of peptide analogs, in which each residue within the minimal determinant was replaced in turn by every one of the other naturally occurring amino acids, revealed either an absolute requirement for the native residue or a very limited degree of replaceability, at seven of the eight positions. Only the N-terminal residue 309V could be replaced with almost any other amino acid without loss of reactivity; in fact, substitution at this position with residues containing bulky side groups enhanced the response. The reactivity of the clone with analogs of the longer peptide 307KYVKQNTLKL316, which induces maximal levels of stimulation, revealed a very different pattern of replaceability for certain residues; in particular, the requirement for a lysine at position 310 was no longer apparent. This study presents a complete analysis of the importance of each individual residue to the integrity of a T cell determinant and provides evidence that the critical requirement for a particular amino acid at a given location may be overridden by N-terminal extension of the minimal determinant. These findings indicate that, within different homologs of the native sequence, particular residues may assume quite different roles.

Sequence Polymorphisms of cDNA Clones Encoding the Mite Allergen <i>Der </i><i>p</i> I

“…Each of the five se quences was unique although they only differed from the others by 1-3 residues. Of the 5 substitutions reported 2 His:Tyr 51 and Glu :Lys 81 were nonconservative with re spect to the predicted influence they would have on the tertiary structure [11] but studies with mutagenized pro tein and peptides have shown that any change can pro foundly affect T cell epitopes including alterations in residues outside the T cell epitopes [12][13][14], Evavold and Allen [13] have for example reported the loss of cpitypic activity by the substitution of Thr and Scr or Gin and Asn for an antihemoglobin T cell clone. Of the 7 epitopes re ported to date for human T-cell responses to Der p I (45-73, 89-117, 85-109,111-139 [15] and 45-67, 94-104,117-143 [16]) three include sequences with a polymorphic residue reported here.…”

Synthetic peptides representing sequences within gp41 of HIV as immunogens for murine T- and B-cell responses

“…In that study, the peptide used had Leu instead of Ile in the third position. Although this is a conservative substitution, our findings concerning T-cell determinant analysis in the influenza virus system [6] show that the replacement Leu ~ Ile within a determinant can significantly affect T-cell recognition.…”

“…Similar technology was used to prepare a set of replacement analogs of the peptide AVERYLKDQQX where X is represented in turn by each of the different amino acids. We have previously shown that the DKP group does not interfere with in vitro presentation of peptides to T cells [6].…”

Identification of a highly promiscuous and an HLA allele‐specific T‐cell epitope in the birch major allergen Bet v 1: HLA restriction, epitope mapping and TCR sequence comparisons

“…In a study of clonal dominance in a TCR repertoire against a HLA-DR3restricted hsp65 peptide, it was reported that this specific MHC class II-peptide complex was able to select for TCR V genes and amino acids in the CDR3 region [27]. For MHC class II peptides, however, the length of the peptide is more flexible [30]. For MHC class II peptides, however, the length of the peptide is more flexible [30].…”

“…On the other hand, conservations within the TCR usage were more generally found in human class-I-restricted responses [28,29], probably a result of the very strict length requirements for MHC class I peptides. For MHC class II peptides, however, the length of the peptide is more flexible [30]. This might lead to different conformations of the MHC-peptide complex and an increase in the availability of TCR contact residues, resulting in a less restricted TCR repertoire.…”