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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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Role of CD4 T cells in NK suppression of anti-viral CD8 T cells, viral control, and immunopathologyPrior to medium (a,b) or high (c–e) dose infection, mice were injected with isotype (Control), anti-NK1.1 (ΔNK), anti-CD4 (ΔCD4), or both (ΔNKΔCD4). a, Viral titers in spleen and (b) number of cytokine-producing NP396–404-specific CD8 T cells (n=5/group, ±s.e.m.) in spleen at day 7 of medium dose infection. c, H&E staining of lung (100×) and (d) survival at day 12 of high dose infection (n=3–5/group).
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Figure 3: Role of CD4 T cells in NK suppression of anti-viral CD8 T cells, viral control, and immunopathologyPrior to medium (a,b) or high (c–e) dose infection, mice were injected with isotype (Control), anti-NK1.1 (ΔNK), anti-CD4 (ΔCD4), or both (ΔNKΔCD4). a, Viral titers in spleen and (b) number of cytokine-producing NP396–404-specific CD8 T cells (n=5/group, ±s.e.m.) in spleen at day 7 of medium dose infection. c, H&E staining of lung (100×) and (d) survival at day 12 of high dose infection (n=3–5/group).

Mentions: The activities of CD4 T cells are important for maintaining CD8 T cell function during LCMV infection12–14. To assess whether CD4 T cells were involved in the NK cell suppression of LCMV-specific CD8 T cells, mice were treated with antibodies to concurrently deplete both NK and CD4 T cells. Whereas depletion of NK cells prior to medium dose LCMV infection resulted in a >200-fold reduction in splenic viral titers at day 7 p.i. relative to control and CD4-depleted (ΔCD4) mice (Fig. 3a), depletion of both NK and CD4 T cells (ΔNKΔCD4) had no effect on viral titers. The increased numbers and enhanced multiple cytokine production by anti-viral CD8 T cells caused by NK cell depletion were also prevented by co-depletion of CD4 T cells (Fig. 3b). In contrast, co-depletion of NK and CD8 T cells did not prevent an increase in IFN-γ+ GP61–80-specific CD4 T cells (Control: 3.8±0.5 % vs. ΔNK: 9.8±0.7 % vs ΔNK/ΔCD8: 10.7±1.6 %, n=3, p<0.05 vs control) at day 12 of medium dose infection.


Natural killer cells act as rheostats modulating antiviral T cells.

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

Role of CD4 T cells in NK suppression of anti-viral CD8 T cells, viral control, and immunopathologyPrior to medium (a,b) or high (c–e) dose infection, mice were injected with isotype (Control), anti-NK1.1 (ΔNK), anti-CD4 (ΔCD4), or both (ΔNKΔCD4). a, Viral titers in spleen and (b) number of cytokine-producing NP396–404-specific CD8 T cells (n=5/group, ±s.e.m.) in spleen at day 7 of medium dose infection. c, H&E staining of lung (100×) and (d) survival at day 12 of high dose infection (n=3–5/group).
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Related In: Results  -  Collection

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

Figure 3: Role of CD4 T cells in NK suppression of anti-viral CD8 T cells, viral control, and immunopathologyPrior to medium (a,b) or high (c–e) dose infection, mice were injected with isotype (Control), anti-NK1.1 (ΔNK), anti-CD4 (ΔCD4), or both (ΔNKΔCD4). a, Viral titers in spleen and (b) number of cytokine-producing NP396–404-specific CD8 T cells (n=5/group, ±s.e.m.) in spleen at day 7 of medium dose infection. c, H&E staining of lung (100×) and (d) survival at day 12 of high dose infection (n=3–5/group).
Mentions: The activities of CD4 T cells are important for maintaining CD8 T cell function during LCMV infection12–14. To assess whether CD4 T cells were involved in the NK cell suppression of LCMV-specific CD8 T cells, mice were treated with antibodies to concurrently deplete both NK and CD4 T cells. Whereas depletion of NK cells prior to medium dose LCMV infection resulted in a >200-fold reduction in splenic viral titers at day 7 p.i. relative to control and CD4-depleted (ΔCD4) mice (Fig. 3a), depletion of both NK and CD4 T cells (ΔNKΔCD4) had no effect on viral titers. The increased numbers and enhanced multiple cytokine production by anti-viral CD8 T cells caused by NK cell depletion were also prevented by co-depletion of CD4 T cells (Fig. 3b). In contrast, co-depletion of NK and CD8 T cells did not prevent an increase in IFN-γ+ GP61–80-specific CD4 T cells (Control: 3.8±0.5 % vs. ΔNK: 9.8±0.7 % vs ΔNK/ΔCD8: 10.7±1.6 %, n=3, p<0.05 vs control) at day 12 of medium dose infection.

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