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Natural killer cells act as rheostats modulating antiviral T cells.

Waggoner SN, Cornberg M, Selin LK, Welsh RM - Nature (2011)

Bottom Line: For instance, NK cells may indirectly regulate T-cell responses by lysing MCMV-infected antigen-presenting cells.We describe a three-way interaction, whereby activated NK cells cytolytically eliminate activated CD4 T cells that affect CD8 T-cell function and exhaustion.Thus, NK cells can act as rheostats, regulating CD4 T-cell-mediated support for the antiviral CD8 T cells that control viral pathogenesis and persistence.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.

ABSTRACT
Antiviral T cells are thought to regulate whether hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections result in viral control, asymptomatic persistence or severe disease, although the reasons for these different outcomes remain unclear. Recent genetic evidence, however, has indicated a correlation between certain natural killer (NK)-cell receptors and progression of both HIV and HCV infection, implying that NK cells have a role in these T-cell-associated diseases. Although direct NK-cell-mediated lysis of virus-infected cells may contribute to antiviral defence during some virus infections--especially murine cytomegalovirus (MCMV) infections in mice and perhaps HIV in humans--NK cells have also been suspected of having immunoregulatory functions. For instance, NK cells may indirectly regulate T-cell responses by lysing MCMV-infected antigen-presenting cells. In contrast to MCMV, lymphocytic choriomeningitis virus (LCMV) infection in mice seems to be resistant to any direct antiviral effects of NK cells. Here we examine the roles of NK cells in regulating T-cell-dependent viral persistence and immunopathology in mice infected with LCMV, an established model for HIV and HCV infections in humans. We describe a three-way interaction, whereby activated NK cells cytolytically eliminate activated CD4 T cells that affect CD8 T-cell function and exhaustion. At high virus doses, NK cells prevented fatal pathology while enabling T-cell exhaustion and viral persistence, but at medium doses NK cells paradoxically facilitated lethal T-cell-mediated pathology. Thus, NK cells can act as rheostats, regulating CD4 T-cell-mediated support for the antiviral CD8 T cells that control viral pathogenesis and persistence.

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LCMV-specific T-cell responses enhanced in NK cell-depleted micea–c, Number (mean±s.e.m.) of LCMV-specific T cells measured by (a,c) IFN- γ+ expression or (b) tetramer-binding at (a,c) various days p.i. (medium dose, n=3/group/day) or at (b) day 5 p.i. (various doses, n=3–11/group). d, Co-production of TNF and IL-2 by gated IFN-γ+ CD4 T cells (day 8 p.i., medium dose) after in vitro stimulation with GP61 peptide. e, Viral titers in liver (n=3–11/group/day, medium dose). f, CFSE dilution by donor (Thy1.1+) CD4 T cells in uninfected and infected (medium dose, day 6 p.i.) Control and ΔNK Thy1.2+ host mice. Control vs. ΔNK mice, *p<0.05, **p<0.01.
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Figure 2: LCMV-specific T-cell responses enhanced in NK cell-depleted micea–c, Number (mean±s.e.m.) of LCMV-specific T cells measured by (a,c) IFN- γ+ expression or (b) tetramer-binding at (a,c) various days p.i. (medium dose, n=3/group/day) or at (b) day 5 p.i. (various doses, n=3–11/group). d, Co-production of TNF and IL-2 by gated IFN-γ+ CD4 T cells (day 8 p.i., medium dose) after in vitro stimulation with GP61 peptide. e, Viral titers in liver (n=3–11/group/day, medium dose). f, CFSE dilution by donor (Thy1.1+) CD4 T cells in uninfected and infected (medium dose, day 6 p.i.) Control and ΔNK Thy1.2+ host mice. Control vs. ΔNK mice, *p<0.05, **p<0.01.

Mentions: As early as day 6 after medium dose infection, the proportion and number of IFN-γ+ LCMV-specific CD8 T cells was increased 2- to 6-fold in mice depleted of NK cells (Fig. 2a and Supplemental Fig. 3), and anti-viral T cells from these mice displayed an enhanced ability to co-produce TNF (Supplemental Fig. 3). The number of NP396–404 tetramer-binding CD8 T cells in the spleen on day 5 p.i. was increased 4- to 20-fold in NK cell-depleted mice relative to non-depleted control mice after infection with all doses of virus (Fig. 2b). The number of virus-specific IFN-γ+ CD4 T cells was also amplified 7-to 20-fold by NK cell depletion compared to control mice on different days after medium dose infection (Fig. 2c). Moreover, co-production of TNF and IL-2 by anti-viral CD4 T cells was augmented by NK cell depletion (Fig. 2d and Supplemental Fig. 3). The increased magnitude of the LCMV-specific T cell response in the absence of NK cells during medium dose infection correlated with rapid viral clearance (Fig. 2e). Depletion of NK cells using a carefully titrated dose of anti-asialo GM1 antibody, which eliminates NK cells but not CD8 T cells11, also enhanced anti-viral CD4 and CD8 T cell responses during medium dose infection (Supplemental Fig. 4).


Natural killer cells act as rheostats modulating antiviral T cells.

Waggoner SN, Cornberg M, Selin LK, Welsh RM - Nature (2011)

LCMV-specific T-cell responses enhanced in NK cell-depleted micea–c, Number (mean±s.e.m.) of LCMV-specific T cells measured by (a,c) IFN- γ+ expression or (b) tetramer-binding at (a,c) various days p.i. (medium dose, n=3/group/day) or at (b) day 5 p.i. (various doses, n=3–11/group). d, Co-production of TNF and IL-2 by gated IFN-γ+ CD4 T cells (day 8 p.i., medium dose) after in vitro stimulation with GP61 peptide. e, Viral titers in liver (n=3–11/group/day, medium dose). f, CFSE dilution by donor (Thy1.1+) CD4 T cells in uninfected and infected (medium dose, day 6 p.i.) Control and ΔNK Thy1.2+ host mice. Control vs. ΔNK mice, *p<0.05, **p<0.01.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3539796&req=5

Figure 2: LCMV-specific T-cell responses enhanced in NK cell-depleted micea–c, Number (mean±s.e.m.) of LCMV-specific T cells measured by (a,c) IFN- γ+ expression or (b) tetramer-binding at (a,c) various days p.i. (medium dose, n=3/group/day) or at (b) day 5 p.i. (various doses, n=3–11/group). d, Co-production of TNF and IL-2 by gated IFN-γ+ CD4 T cells (day 8 p.i., medium dose) after in vitro stimulation with GP61 peptide. e, Viral titers in liver (n=3–11/group/day, medium dose). f, CFSE dilution by donor (Thy1.1+) CD4 T cells in uninfected and infected (medium dose, day 6 p.i.) Control and ΔNK Thy1.2+ host mice. Control vs. ΔNK mice, *p<0.05, **p<0.01.
Mentions: As early as day 6 after medium dose infection, the proportion and number of IFN-γ+ LCMV-specific CD8 T cells was increased 2- to 6-fold in mice depleted of NK cells (Fig. 2a and Supplemental Fig. 3), and anti-viral T cells from these mice displayed an enhanced ability to co-produce TNF (Supplemental Fig. 3). The number of NP396–404 tetramer-binding CD8 T cells in the spleen on day 5 p.i. was increased 4- to 20-fold in NK cell-depleted mice relative to non-depleted control mice after infection with all doses of virus (Fig. 2b). The number of virus-specific IFN-γ+ CD4 T cells was also amplified 7-to 20-fold by NK cell depletion compared to control mice on different days after medium dose infection (Fig. 2c). Moreover, co-production of TNF and IL-2 by anti-viral CD4 T cells was augmented by NK cell depletion (Fig. 2d and Supplemental Fig. 3). The increased magnitude of the LCMV-specific T cell response in the absence of NK cells during medium dose infection correlated with rapid viral clearance (Fig. 2e). Depletion of NK cells using a carefully titrated dose of anti-asialo GM1 antibody, which eliminates NK cells but not CD8 T cells11, also enhanced anti-viral CD4 and CD8 T cell responses during medium dose infection (Supplemental Fig. 4).

Bottom Line: For instance, NK cells may indirectly regulate T-cell responses by lysing MCMV-infected antigen-presenting cells.We describe a three-way interaction, whereby activated NK cells cytolytically eliminate activated CD4 T cells that affect CD8 T-cell function and exhaustion.Thus, NK cells can act as rheostats, regulating CD4 T-cell-mediated support for the antiviral CD8 T cells that control viral pathogenesis and persistence.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.

ABSTRACT
Antiviral T cells are thought to regulate whether hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections result in viral control, asymptomatic persistence or severe disease, although the reasons for these different outcomes remain unclear. Recent genetic evidence, however, has indicated a correlation between certain natural killer (NK)-cell receptors and progression of both HIV and HCV infection, implying that NK cells have a role in these T-cell-associated diseases. Although direct NK-cell-mediated lysis of virus-infected cells may contribute to antiviral defence during some virus infections--especially murine cytomegalovirus (MCMV) infections in mice and perhaps HIV in humans--NK cells have also been suspected of having immunoregulatory functions. For instance, NK cells may indirectly regulate T-cell responses by lysing MCMV-infected antigen-presenting cells. In contrast to MCMV, lymphocytic choriomeningitis virus (LCMV) infection in mice seems to be resistant to any direct antiviral effects of NK cells. Here we examine the roles of NK cells in regulating T-cell-dependent viral persistence and immunopathology in mice infected with LCMV, an established model for HIV and HCV infections in humans. We describe a three-way interaction, whereby activated NK cells cytolytically eliminate activated CD4 T cells that affect CD8 T-cell function and exhaustion. At high virus doses, NK cells prevented fatal pathology while enabling T-cell exhaustion and viral persistence, but at medium doses NK cells paradoxically facilitated lethal T-cell-mediated pathology. Thus, NK cells can act as rheostats, regulating CD4 T-cell-mediated support for the antiviral CD8 T cells that control viral pathogenesis and persistence.

Show MeSH
Related in: MedlinePlus