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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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NK cells influence T cell-dependent pathology and viral persistence during LCMV infectionC57BL/6 mice treated with IgG2a (Control) or anti-NK1.1 (ΔNK) were infected with low (5×104 PFU), medium (2×105 PFU), or high (2×106 PFU) doses of LCMV. a, Weight loss (mean±s.e.m.) during infection (n=3–43/group/day), *p<0.05, **p<0.01. b, H&E staining of lung (400×) at day 15 p.i., c, Survival after high or medium dose infection. d, Viral titers (mean±s.e.m) after low (day 7, n=3/group), medium (day 15, n=9–15/group), or high (day 8, n=3/group) dose infection. Dotted line represents limit of detection.
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Figure 1: NK cells influence T cell-dependent pathology and viral persistence during LCMV infectionC57BL/6 mice treated with IgG2a (Control) or anti-NK1.1 (ΔNK) were infected with low (5×104 PFU), medium (2×105 PFU), or high (2×106 PFU) doses of LCMV. a, Weight loss (mean±s.e.m.) during infection (n=3–43/group/day), *p<0.05, **p<0.01. b, H&E staining of lung (400×) at day 15 p.i., c, Survival after high or medium dose infection. d, Viral titers (mean±s.e.m) after low (day 7, n=3/group), medium (day 15, n=9–15/group), or high (day 8, n=3/group) dose infection. Dotted line represents limit of detection.

Mentions: Intravenous (i.v.) inoculation of C57BL/6 mice with a low (5×104 PFU), medium (2×105 PFU), or high (2×106 PFU) dose of LCMV, strain Clone 13, resulted in different degrees of pathology, as indicated by weight loss (Fig. 1a) and by histological analysis of lung sections at day 15 p.i. (Fig. 1b). The high dose caused a precipitous drop in body weight during the first week of infection (Fig. 1a, right), but, thereafter, clonal exhaustion and deletion of LCMV-specific T cells resulted in a persistent infection9–10 associated with minimal lung pathology (Fig. 1b, Right) and 100% (77 of 77) survival (Fig. 1c, Top). Selective depletion of NK cells using 25 µg of anti-NK1.1 mAb (Supplemental Fig. 1) one day prior to high dose infection resulted in 58% (35 of 65) mortality between days 9 and 13 of infection (Fig. 1c, Top) associated with severe pulmonary edema (data not shown) and reduced viral titers by day 7 p.i. (Fig. 1d, Right). Under these high dose conditions, therefore, the presence of NK cells promoted persistence and prevented mortality.


Natural killer cells act as rheostats modulating antiviral T cells.

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

NK cells influence T cell-dependent pathology and viral persistence during LCMV infectionC57BL/6 mice treated with IgG2a (Control) or anti-NK1.1 (ΔNK) were infected with low (5×104 PFU), medium (2×105 PFU), or high (2×106 PFU) doses of LCMV. a, Weight loss (mean±s.e.m.) during infection (n=3–43/group/day), *p<0.05, **p<0.01. b, H&E staining of lung (400×) at day 15 p.i., c, Survival after high or medium dose infection. d, Viral titers (mean±s.e.m) after low (day 7, n=3/group), medium (day 15, n=9–15/group), or high (day 8, n=3/group) dose infection. Dotted line represents limit of detection.
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Related In: Results  -  Collection

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

Figure 1: NK cells influence T cell-dependent pathology and viral persistence during LCMV infectionC57BL/6 mice treated with IgG2a (Control) or anti-NK1.1 (ΔNK) were infected with low (5×104 PFU), medium (2×105 PFU), or high (2×106 PFU) doses of LCMV. a, Weight loss (mean±s.e.m.) during infection (n=3–43/group/day), *p<0.05, **p<0.01. b, H&E staining of lung (400×) at day 15 p.i., c, Survival after high or medium dose infection. d, Viral titers (mean±s.e.m) after low (day 7, n=3/group), medium (day 15, n=9–15/group), or high (day 8, n=3/group) dose infection. Dotted line represents limit of detection.
Mentions: Intravenous (i.v.) inoculation of C57BL/6 mice with a low (5×104 PFU), medium (2×105 PFU), or high (2×106 PFU) dose of LCMV, strain Clone 13, resulted in different degrees of pathology, as indicated by weight loss (Fig. 1a) and by histological analysis of lung sections at day 15 p.i. (Fig. 1b). The high dose caused a precipitous drop in body weight during the first week of infection (Fig. 1a, right), but, thereafter, clonal exhaustion and deletion of LCMV-specific T cells resulted in a persistent infection9–10 associated with minimal lung pathology (Fig. 1b, Right) and 100% (77 of 77) survival (Fig. 1c, Top). Selective depletion of NK cells using 25 µg of anti-NK1.1 mAb (Supplemental Fig. 1) one day prior to high dose infection resulted in 58% (35 of 65) mortality between days 9 and 13 of infection (Fig. 1c, Top) associated with severe pulmonary edema (data not shown) and reduced viral titers by day 7 p.i. (Fig. 1d, Right). Under these high dose conditions, therefore, the presence of NK cells promoted persistence and prevented mortality.

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