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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 rapidly eliminate activated CD4 T cellsa–f, in vivo cytotoxicity assays were performed as described in Methods using donor cells from NK cell-depleted (a–f) WT (Ly5.1+) or (d) lpr mice 4 days p.i. with (a–e) medium dose LCMV or (f) other viruses. Recovery of donor T cells was examined 5 h after transfer into control or NK-depleted (ΔNK) Ly5.2+ mice (a, n=21–28/group; b–f, n=3–5/group). Host mice were uninfected or inoculated with (a,c,d,f) medium dose LCMV (day 3 p.i.), (b) various doses of LCMV (day 3 p.i.), or (e) PV (day 2), MHV (day 3), and pI:C (day 1). a,b,d–f, lysis (mean±s.e.m.) of donor T cells in infected relative to uninfected recipient mice; control vs. ΔNK mice, *p<0.05. c, AnnexinV-reactivity of donor (Ly5.1+) and host (Ly5.1−) CD4 T cells. f, Proposed model connecting NK-cell killing of CD4 T cells to CD8 T cells and infection outcome in the presence of NK cells.
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Figure 4: NK cells rapidly eliminate activated CD4 T cellsa–f, in vivo cytotoxicity assays were performed as described in Methods using donor cells from NK cell-depleted (a–f) WT (Ly5.1+) or (d) lpr mice 4 days p.i. with (a–e) medium dose LCMV or (f) other viruses. Recovery of donor T cells was examined 5 h after transfer into control or NK-depleted (ΔNK) Ly5.2+ mice (a, n=21–28/group; b–f, n=3–5/group). Host mice were uninfected or inoculated with (a,c,d,f) medium dose LCMV (day 3 p.i.), (b) various doses of LCMV (day 3 p.i.), or (e) PV (day 2), MHV (day 3), and pI:C (day 1). a,b,d–f, lysis (mean±s.e.m.) of donor T cells in infected relative to uninfected recipient mice; control vs. ΔNK mice, *p<0.05. c, AnnexinV-reactivity of donor (Ly5.1+) and host (Ly5.1−) CD4 T cells. f, Proposed model connecting NK-cell killing of CD4 T cells to CD8 T cells and infection outcome in the presence of NK cells.

Mentions: We utilized a modified in vivo cytotoxicity assay by injecting splenocytes from medium dose-infected NK cell-depleted mice (Ly5.1+, day 4 p.i.) into medium dose-infected NK cell-depleted (ΔNK) or isotype IgG2a-treated (Control) recipient mice (Ly5.2+, day 3 p.i.). After 5 hours, similar proportions of total donor T (Control: 0.16±0.03 % vs. ΔNK: 0.15±0.02 %, n=21, p=0.80) and B cells (Control: 1.8±0.2 % vs. ΔNK: 1.7±0.2 %, n=21, p=0.88) were recovered from infected recipients, regardless of NK cell depletion. Likewise, recovery of activated (CD44hi CD43(1B11)+) donor CD8 T cells was similar from spleens of Control and ΔNK mice, with minimal loss relative to uninfected control mice (Fig. 4a). In contrast, there was a substantial loss of activated donor CD4 T cells in infected relative to uninfected recipients, and this loss was prevented by depletion of NK cells (Fig. 4a). The magnitude of NK cell-dependent loss of activated donor CD4 T cells was similar in low-, medium-, and high dose-infected recipients (Fig. 4b). More activated CD4 T cells, both donor- and host-derived, in infected (Control) mice stained positively for the apoptosis indicator, AnnexinV, in comparison to naive donor CD4 T cells or to activated donor CD4 T cells in medium dose-infected ΔNK recipient mice (Fig. 4c). In contrast to activated donor CD4 T cells, the recoveries of naïve (CD44low) phenotype CD4 and CD8 donor T cells were not altered by NK cell-depletion (data not shown). These data indicate that NK cells in WT mice selectively and rapidly target activated CD4 T cells for elimination during LCMV infection.


Natural killer cells act as rheostats modulating antiviral T cells.

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

NK cells rapidly eliminate activated CD4 T cellsa–f, in vivo cytotoxicity assays were performed as described in Methods using donor cells from NK cell-depleted (a–f) WT (Ly5.1+) or (d) lpr mice 4 days p.i. with (a–e) medium dose LCMV or (f) other viruses. Recovery of donor T cells was examined 5 h after transfer into control or NK-depleted (ΔNK) Ly5.2+ mice (a, n=21–28/group; b–f, n=3–5/group). Host mice were uninfected or inoculated with (a,c,d,f) medium dose LCMV (day 3 p.i.), (b) various doses of LCMV (day 3 p.i.), or (e) PV (day 2), MHV (day 3), and pI:C (day 1). a,b,d–f, lysis (mean±s.e.m.) of donor T cells in infected relative to uninfected recipient mice; control vs. ΔNK mice, *p<0.05. c, AnnexinV-reactivity of donor (Ly5.1+) and host (Ly5.1−) CD4 T cells. f, Proposed model connecting NK-cell killing of CD4 T cells to CD8 T cells and infection outcome in the presence of NK cells.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: NK cells rapidly eliminate activated CD4 T cellsa–f, in vivo cytotoxicity assays were performed as described in Methods using donor cells from NK cell-depleted (a–f) WT (Ly5.1+) or (d) lpr mice 4 days p.i. with (a–e) medium dose LCMV or (f) other viruses. Recovery of donor T cells was examined 5 h after transfer into control or NK-depleted (ΔNK) Ly5.2+ mice (a, n=21–28/group; b–f, n=3–5/group). Host mice were uninfected or inoculated with (a,c,d,f) medium dose LCMV (day 3 p.i.), (b) various doses of LCMV (day 3 p.i.), or (e) PV (day 2), MHV (day 3), and pI:C (day 1). a,b,d–f, lysis (mean±s.e.m.) of donor T cells in infected relative to uninfected recipient mice; control vs. ΔNK mice, *p<0.05. c, AnnexinV-reactivity of donor (Ly5.1+) and host (Ly5.1−) CD4 T cells. f, Proposed model connecting NK-cell killing of CD4 T cells to CD8 T cells and infection outcome in the presence of NK cells.
Mentions: We utilized a modified in vivo cytotoxicity assay by injecting splenocytes from medium dose-infected NK cell-depleted mice (Ly5.1+, day 4 p.i.) into medium dose-infected NK cell-depleted (ΔNK) or isotype IgG2a-treated (Control) recipient mice (Ly5.2+, day 3 p.i.). After 5 hours, similar proportions of total donor T (Control: 0.16±0.03 % vs. ΔNK: 0.15±0.02 %, n=21, p=0.80) and B cells (Control: 1.8±0.2 % vs. ΔNK: 1.7±0.2 %, n=21, p=0.88) were recovered from infected recipients, regardless of NK cell depletion. Likewise, recovery of activated (CD44hi CD43(1B11)+) donor CD8 T cells was similar from spleens of Control and ΔNK mice, with minimal loss relative to uninfected control mice (Fig. 4a). In contrast, there was a substantial loss of activated donor CD4 T cells in infected relative to uninfected recipients, and this loss was prevented by depletion of NK cells (Fig. 4a). The magnitude of NK cell-dependent loss of activated donor CD4 T cells was similar in low-, medium-, and high dose-infected recipients (Fig. 4b). More activated CD4 T cells, both donor- and host-derived, in infected (Control) mice stained positively for the apoptosis indicator, AnnexinV, in comparison to naive donor CD4 T cells or to activated donor CD4 T cells in medium dose-infected ΔNK recipient mice (Fig. 4c). In contrast to activated donor CD4 T cells, the recoveries of naïve (CD44low) phenotype CD4 and CD8 donor T cells were not altered by NK cell-depletion (data not shown). These data indicate that NK cells in WT mice selectively and rapidly target activated CD4 T cells for elimination during LCMV 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