Highly restricted T-cell receptor repertoire in the CD8+ T-cell response against an HIV-1 epitope with a stereotypic amino acid substitution.

In peripheral blood mononuclear cells (PBMCs) from HIV-1-positive patients, we sought to identify CD8+ T-cell populations and the corresponding T-cell receptor (TCR) repertoires that react to an immunogenic cytotoxic T lymphocyte (CTL) epitope with or without an escape mutation. PBMCs from HLA-A*2402(A24)-positive patients were stimulated with peptides representing a wild-type CTL epitope in the HIV-1 Nef protein [Nef138-10(wt)] or an escape mutant with a Y to F (Y139F) substitution at the second position [Nef138-10(2F)]. Cultured PBMCs were stained with peptide-major histocompatibility complex tetramers containing Nef138-10(wt) or Nef138-10(2F) sequences. After in-vitro stimulation of PBMCs with cognate peptides, the CD8+ T-cell population was sorted into different fractions: positive only to the wild-type tetramer (wt-positive), positive only to the mutant tetramer (2F-positive), and positive to both wt-tetramers and mutant-tetramers (dual-positive). TCR repertoires of sorted epitope-specific CD8+ T-cell populations were determined by sequencing. A 2F-positive population was rarely observed under our culture and staining conditions. The wt-positive CD8+ T-cell populations had a diverse TCR repertoire, but the TCR repertoires in dual-positive CD8+ populations were highly restricted. In the dual-positive CD8+ T-cell populations, most clonotypes used the TRBV4-1 and TRBJ2-7 gene segments for the TCR beta-chain and the TRAV8-3 and TRAJ40-1 for the TCR alpha-chain. The CDR3 region of the TCR beta-chain showed little variation. These results provide an example of restricted TCR repertoire in a specific CTL response against the escaping epitope. We speculate that impairment of antigen presentation in escaping viruses may underlie the restricted repertoire.

Citation

Eriko Miyazaki, Ai Kawana-Tachikawa, Mariko Tomizawa, Jun-ichi Nunoya, Takashi Odawara, Takeshi Fujii, Yi Shi, George Fu Gao, Aikichi Iwamoto. Highly restricted T-cell receptor repertoire in the CD8+ T-cell response against an HIV-1 epitope with a stereotypic amino acid substitution. AIDS (London, England). 2009 Mar 27;23(6):651-60

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PMID: 19279440

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