Lichterfeld, M;
Kavanagh, DG;
Williams, KL;
Moza, B;
Mui, SK;
Miura, T;
Sivamurthy, R;
Allgaier, R;
Pereyra, F;
Trocha, A;
et al.
Lichterfeld, M; Kavanagh, DG; Williams, KL; Moza, B; Mui, SK; Miura, T; Sivamurthy, R; Allgaier, R; Pereyra, F; Trocha, A; Feeney, M; Gandhi, RT; Rosenberg, ES; Altfeld, M; Allen, TM; Allen, R; Walker, BD; Sundberg, EJ; Yu, XG
(2007)
A viral CTL escape mutation leading to immunoglobulin-like transcript 4-mediated functional inhibition of myelomonocytic cells.
JOURNAL OF EXPERIMENTAL MEDICINE, 204 (12).
2813 - 2824 (12).
ISSN 0022-1007
https://doi.org/10.1084/jem.20061865
SGUL Authors: Allen, Rachel Louise
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Abstract
Viral mutational escape can reduce or abrogate recognition by the T cell receptor (TCR) of virus-specific CD8+ T cells. However, very little is known about the impact of cytotoxic T lymphocyte (CTL) epitope mutations on interactions between peptide–major histocompatibility complex (MHC) class I complexes and MHC class I receptors expressed on other cell types. Here, we analyzed a variant of the immunodominant human leukocyte antigen (HLA)-B2705–restricted HIV-1 Gag KK10 epitope (KRWIILGLNK) with an L to M amino acid substitution at position 6 (L6M), which arises as a CTL escape variant after primary infection but is sufficiently immunogenic to elicit a secondary, de novo HIV-1–specific CD8+ T cell response with an alternative TCR repertoire in chronic infection. In addition to altering recognition by HIV-1–specific CD8+ T cells, the HLA-B2705–KK10 L6M complex also exhibits substantially increased binding to the immunoglobulin-like transcript (ILT) receptor 4, an inhibitory MHC class I–specific receptor expressed on myelomonocytic cells. Binding of the B2705–KK10 L6M complex to ILT4 leads to a tolerogenic phenotype of myelomonocytic cells with lower surface expression of dendritic cell (DC) maturation markers and co-stimulatory molecules. These data suggest a link between CTL-driven mutational escape, altered recognition by innate MHC class I receptors on myelomonocytic cells, and functional impairment of DCs, and thus provide important new insight into biological consequences of viral sequence diversification
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