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.

11 Reads
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In response to antigen naive CD8+, T cells differentiate into effector cells, which express Natural killer (NK) receptors, lose CD28 expression, and die by apoptosis. However, in smaller quantities, the cells are retained for subsequent exposure to the same antigen. Knowledge is limited regarding whether the percentages of CD28-, Effector memory (EMRAnull/dim), and the CD16+/CD56 + CD8+ T cells of women with low-grade cervical lesions are altered at a systemic level. We enrolled in this study women controls and women with Human papilloma virus infection (HPV-I) without associated cellular neoplastic changes and with Cervical Intraepithelial Neoplastic-I (CIN-I). Flow cytometry (FC) was performed for measurement of CD28-, memory subset, and NK-like CD8 + T cells, and IL-17, IFN-gamma, Tumor necrosis factor (TNF)-alpha, Interleukin (IL)-10, IL-6, IL-4, and IL-2. Finally, we genotyped the HPV. The CIN-I group increased the CD8 + CD28− and CD16+/56+ T cell percentage compared with that of HPV-I and controls (p <0.01), and CD8 + CCR7-CD45RAnull/dim (EMRAnull/dim) T cells were also increased in the CIN-I group compared with the controls (p <0.01). These two study groups were HPV- genotyped; 49% were HPV18+, and we did not observe differences in cytokine levels among all groups. Increased levels of CD28-, EMRAnull/dim, and CD16+/CD56 + CD8+ T cells of peripheral blood in women with CIN-I may be associated with persistent HPV infection and could exert an influence on progression to cervical cancer.
    Cancer Cell International 09/2014; 14(1):97. DOI:10.1186/s12935-014-0097-5 · 2.77 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Virology 01/2013; 435(1):37-45. DOI:10.1016/j.virol.2012.10.005 · 3.32 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: CD8 memory T cells can play a critical role in protection against repeated exposure to infectious agents such as viruses, yet can also contribute to the immunopathology associated with these pathogens. Understanding the mechanisms that control effective memory responses has important ramifications for vaccine design and in the management of adverse immune reactions. Recent studies have implicated several members of the tumor necrosis factor receptor (TNFR) family as key stimulatory and inhibitory molecules involved in the regulation of CD8 T cells. In this review, we discuss their control of the generation, persistence, and reactivation of CD8 T cells during virus infection.
    Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 04/2010; 30(4):205-18. DOI:10.1089/jir.2010.0026 · 2.00 Impact Factor
Show more


11 Reads
Available from