High Frequencies of Virus-Specific CD8(+) T-Cell Precursors

Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Journal of Virology (Impact Factor: 4.44). 10/2009; 83(24):12907-16. DOI: 10.1128/JVI.01722-09
Source: PubMed


A productive CD8(+) T-cell response to a viral infection requires rapid division and proliferation of virus-specific CD8(+) T cells. Tetramer-based enrichment assays have recently given estimates of the numbers of peptide-major histocompatibility complex-specific CD8(+) T cells in naïve mice, but precursor frequencies for entire viruses have been examined only by using in vitro limiting-dilution assays (LDAs). To examine CD8(+) T-cell precursor frequencies for whole viruses, we developed an in vivo LDA and found frequencies of naïve CD8(+) T-cell precursors of 1 in 1,444 for vaccinia virus (VV) ( approximately 13,850 VV-specific CD8(+) T cells per mouse) and 1 in 2,958 for lymphocytic choriomeningitis virus (LCMV) ( approximately 6,761 LCMV-specific CD8(+) T cells per mouse) in C57BL/6J mice. In mice immune to VV, the number of VV-specific precursors, not surprisingly, dramatically increased to 1 in 13 ( approximately 1,538,462 VV-specific CD8(+) T cells per mouse), consistent with estimates of VV-specific memory T cells. In contrast, precursor numbers for LCMV did not increase in VV-immune mice (1 in 4,562, with approximately 4,384 LCMV-specific CD8(+) T cells per VV-immune mouse). Using H-2D(b)-restricted LCMV GP33-specific P14-transgenic T cells, we found that, after donor T-cell take was accounted for, approximately every T cell transferred underwent a full proliferative expansion in response to LCMV infection. This high efficiency was also seen with memory populations, suggesting that most antigen-specific T cells will proliferate extensively at a limiting dilution in response to infections. These results show that frequencies of naïve and memory CD8(+) T cell precursors for whole viruses can be remarkably high.

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    • "The primary function of cytotoxic T lymphocytes and Natural killer (NK) cells is to detect and eliminate virus-infected or -transformed cells [4,5]. The immune response triggered by NK cells involves a complex interaction of receptors, perforins, granzymes, and CD8+ effector T cells, which recognize antigens by the T cell receptor [6]. A productive CD8(+) T-cell response to a viral infection requires rapid division and proliferation of virus-specific CD8(+) T cells [6]. "
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    • "NK cells patrol the host at a moderate state of activation and at a relatively high frequency ( 15% of peripheral blood lymphocytes), but will proliferate and become even more active during a viral infection (Biron et al., 1983; Welsh, 1978). However, immunologically naı¨ve T cells specific to any peptide epitope exist at low frequency ( 1/50,000) and in an inactive naı¨ve state and require a substantial clonal expansion to increase in numbers and functions sufficient to control of infection (Blattman et al., 2002; Seedhom et al., 2009). Innate cytokines such as the type 1 interferons (IFN), IL-12, and IL-15 are rapidly induced during viral infections and can stimulate the activation and proliferation of NK cells and greatly augment the proliferation of T cells (Biron, 1995). "
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    ABSTRACT: Viral infections characteristically induce a cytokine-driven activated natural killer (NK) cell response that precedes an antigen-driven T cell response. These NK cells can restrain some but not all viral infections by attacking virus-infected cells and can thereby provide time for an effective T cell response to mobilize. Recent studies have revealed an additional immunoregulatory role for the NK cells, where they inhibit the size and functionality of the T cell response, regardless of whether the viruses are themselves sensitive to NK cells. This subsequent change in T cell dynamics can alter patterns of immunopathology and persistence and implicates NK cells as rheostat-like regulators of persistent infections.
    Full-text · Article · Jan 2013 · Virology
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    • "The fi rst phase begins when circulating peripheral naïve CD8 T cells recognize, via their T-cell receptor (TCR), antigenic peptides bound to major histocompatibility complex (MHC) class I complexes on the surface of mature dendritic cells (DCs). Studies using a number of different experimental approaches calculated that the precursor frequencies of naive virus-specifi c CD8 T cells range from 1 to 5 in 100,000 (Blattman and others 2002), but in some cases can reach as high as 1 in 1,444 for certain viruses such as vaccinia virus (VACV) and 1 in 2,985 for lymphocytic choriomeningitis virus (LCMV) (Seedhom and others 2009). After antigen recognition, these small numbers of antigen-specifi c precursor CD8 T cells undergo about 11 to 15 divisions to become a large population of cells found at the peak of the primary response, which is typically between Days 6 and 7 postinfection (Butz and Bevan 1998; Doherty 1998; Flynn and others 1998; Murali-Krishna and others 1998). "
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