Human HLA-A0201-restricted cytotoxic T lymphocyte recognition of influenza A is dominated by T cells bearing the V beta 17 gene segment.

Abstract

SummaryThe major histocompatibility complex class I-restricted cytotoxic T lymphocyte (CTL) response is important in the clearance of viral infections in humans. After influenza A infection, a peptide from the matrix protein, M58-66, is presented in the context of the MHC allele HLA-A0201 and the resulting CTL response is detectable in most HLA-A0201 subjects. An initial study suggested that M58-66-specific CTL clones show conserved T cell receptor (TCR) c~ and gene segments. We have addressed the significance of this observation by determining the expression of V317 during the development of M58-66-specific CTL lines in 21 unrelated HLA-A0201 subjects, and analyzing TCR usage by M58-66-specific CTL clones. TCR V317 was the dominant V3 segment used and CD8 V~17 expansion correlated with M58-66-specific lysis. Limiting dilution analysis from five subjects showed the M58-66 CTL precursor frequency to vary between 1/54,000 and less than 1/250,000, and that up to 85% of the matrix peptide (M58-66)-specific CTL used the V317 gene segment. The M58-66 specific CTL response was dependent on previous viral exposure and specific V317 expansion, as it was not found in cord blood, despite a readily expandable V317 + CD8 + T cell subpopulation. Sequence analysis of 38 M58-66-specific V317 transcripts from 13 subjects revealed extensive conservation in the CDR3 region including conservation of an arginine-serine motif. To test the dependence of this CTL response on the V[317 gene segment, peripheral blood lymphocytes were depleted of CD8 + TCR V317 + cells, before the generation of M58-66-specific CTL. In most cases such depletion blocked or severely reduced the generation of the M58-66-specific response, and under limiting dilution conditions could abolish M58-66-specific CTL precursors. These studies reveal the dependence of this natural human immune response on a particular TCR gene segment.

Frequent Contribution of T Cell Clonotypes with Public TCR Features to the Chronic Response Against a Dominant EBV-Derived Epitope: Application to Direct Detection of Their Molecular Imprint on the Human Peripheral T Cell Repertoire

“…In particular, several public BV4, BV16, and AV15 transcripts comprised VD, DJ, or VJ joints devoid of nongermline nucleotides; among them, one BV4BD2BJ1S4 transcript shared by three donors was totally devoid of N nucleotides at both VD and DJ joints, and one AV15S1AJ37 joint shared by two donors was generated by so-called homologous region guided recombination (43) (Table VII). Therefore, enzymatic constraints linked to the recombination machinery may favor the generation of some public rearrangements before Ag exposure, as suggested by several previous studies (12)(13)(14)(15). However, several public sequences also comprised highly conserved residues that were mainly N encoded; this was typically the case for public BV16 sequences, which showed highly diverse nucleotide sequences due to extensive N addition at the VD joints despite full conservation of their amino acid sequence (Table VII).…”

Cross-presenting human γδ T cells induce robust CD8 + αβ T cell responses

“…M1p58-66-specific T cells became detectable (0.1-0.3% among total CD8 ϩ ␣␤ T cells), as assessed by tetramer staining, and this T cell subset was maintained during secondary expansion, permitting their further examination (see below). Proliferation responses were remarkable, because the frequency of M1p58-66-specific (M1p58-66-tetramer ϩ ) cells in the starting population of naïve blood CD8 ϩ T cells was below the level of detection (Ͻ1/50,000) (22). In contrast to ␥␦ T-APCs, the responses of naïve CD8 ϩ ␣␤ T cells to M1 cross-presenting DCs were highly variable or undetectable (example in Fig.…”

T‐Cell Receptor BJ Gene Segment Expression in Human Umbilical Cord Blood CD4+ and CD8+ T‐Cell Subsets

“…Three complementarity-determining regions (CDR1, CDR2 and CDR3) have been defined for each of the two TCR chains. Although challenged by some recent studies [3][4][5][6], the portion of the TCR essentially responsible for interaction with the antigenic peptide has been claimed to lie in the CDR3 loops of the two variable regions [1,[7][8][9][10][11][12]. By definition, part of the CDR3 region is encoded by a given J gene segment [7].…”