IL-10 Suppression of NK/DC Crosstalk Leads to Poor Priming of MCMV-Specific CD4 T Cells and Prolonged MCMV Persistence

Mandarić, Sanja; Walton, Senta M.; Rülicke, Thomas; Richter, Kirsten; Girard-Madoux, Mathilde J.H.; Clausen, Björn E.; Zurunic, Antonija; Kamanaka, Masahito; Flavell, Richard A.; Jonjić, Stipan; Oxenius, Annette

doi:10.1371/journal.ppat.1002846

Cited by 75 publications

(92 citation statements)

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“…37 This was associated with changes in CXCR3-driven migration of NK cells to the regional lymph nodes which can affect NK-dendritic cell crosstalk necessary for priming MCMV-specific CD4 + T cells. 38 In our study, we found that in contrast to this observation, Cxcr3 mRNA was upregulated, consistent with the higher expression of CXCR3 on the less mature CD27 high M1 NK cells. 39,40 Indeed, the number of NK cells that localized in the lung in response to a B16F10 tumor cells which are likely to express the ligand for NKp46 was not reduced in Ly5.1 C14R mice (SI Appendix, Figure S4) and the cytolytic machinery was intact.…”

Section: Discussionsupporting

confidence: 86%

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

et al. 2018

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NKp46 (CD335) is a surface receptor shared by both human and mouse natural killer (NK) cells and innate lymphoid cells (ILCs) that transduces activating signals necessary to eliminate virus-infected cells and tumors. Here, we describe a spontaneous point mutation of cysteine to arginine (C14R) in the signal peptide of the NKp46 protein in congenic Ly5.1 mice and the newly generated NCRB6C14R strain. Ly5.1C14R NK cells expressed similar levels of Ncr1 mRNA as C57BL/6, but showed impaired surface NKp46 and reduced ability to control melanoma tumors in vivo. Expression of the mutant NKp46C14R in 293T cells showed that NKp46 protein trafficking to the cell surface was compromised. Although Ly5.1C14R mice had normal number of NK cells, they showed an increased number of early maturation stage NK cells. CD49a+ILC1s were also increased but these cells lacked the expression of TRAIL. ILC3s that expressed NKp46 were not detectable and were not apparent when examined by T-bet expression. Thus, the C14R mutation reveals that NKp46 is important for NK cell and ILC differentiation, maturation and function.SignificanceInnate lymphoid cells (ILCs) play important roles in immune protection. Various subsets of ILCs express the activating receptor NKp46 which is capable of recognizing pathogen derived and tumor ligands and is necessary for immune protection. Here, we describe a spontaneous point mutation in the signal peptide of the NKp46 protein in congenic Ly5.1 mice which are widely used for tracking cells in vivo. This Ncr1 C14R mutation impairs NKp46 surface expression resulting in destabilization of Ncr1 and accumulation of NKp46 in the endoplasmic reticulum. Loss of stable NKp46 expression impaired the maturation of NKp46+ ILCs and altered the expression of TRAIL and T-bet in ILC1 and ILC3, respectively.

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Section: Discussionsupporting

confidence: 86%

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

et al. 2018

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“…However, in mice, with the exception of the salivary gland tissue, CD4 + T cells were so far considered not to exert direct antiviral functions in other organs upon MCMV infection [33]. These studies relied on experimental protocols where effector cell populations comprising total CD4 + T cells were isolated from MCMV-immune donor mice and were used for subsequent adoptive transfer experiments [15].Considering the low frequency of endogenous IFN-γ-producing MCMV-specific CD4 + T effector cells in peripheral tissues [18], in particular in the spleen, this protocol presumably did not retrieve sufficient numbers of IFN-γ-producing virus-specific CD4 + T cells. The fact that only a high number of M25-specific CD4 + T cells mediated antiviral protection is in line with this assumption and represents a challenging factor for human immunotherapy protocols, which largely rely on enrichment of virus-specific CD4 + T cells from CMV-immune donor peripheral blood.…”

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confidence: 99%

Adoptive transfer of cytomegalovirus‐specific effector CD4⁺T cells provides antiviral protection from murine CMV infection

et al. 2013

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Cytomegalovirus (CMV) infects a majority of the human population and establishes a lifelong persistence. CMV infection is usually asymptomatic but the virus carries pathogenic potential and causes severe disease in immunocompromised individuals. T-cell-mediated immunity plays an essential role in control of CMV infection and adoptive transfer of CMVspecific CD8 + T cells restores viral immunity in immunosuppressed patients but a role for CD4 + T cells remains elusive. Here, we analyzed in adoptive transfer studies the features and antiviral functions of virus-specific CD4 + T cells during primary murine CMV (MCMV) infection. MCMV-specific CD4 + T cells expanded upon MCMV infection and displayed an effector phenotype and function. Adoptive transfer of in vivo activated MCMV-specific CD4 + T cells to immune-compromised mice was protective during pathogenic MCMVinfection and IFN-γ was a crucial mediator of this protective capacity. Moreover, cotransfer of low doses of both MCMV-specific CD4 + T cells and CD8 + T cells synergized in control of lytic viral replication in immune-compromised mice. Our data reveal a pivotal antiviral role for virus-specific CD4 + T cells in protection from pathogenic CMV infection and provide evidence for their antiviral therapeutic potential. Keywords: Adoptive immunotherapy r CD4 + T cells r Cytomegalovirus infectionAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionImmunity to viral infections relies on effector mechanisms exerted by different components of the immune system. Despite the prominent roles of cytotoxic CD8 + T cells and neutralizing antibodies in controlling viral infections, there is growing evidence for an antiviral role of CD4 + helper T cells, not only in provision of help to other effector cells, but also in exertion of direct antiviral functions either by secretion of cytokines or exertion of cytotoxicity [1]. CD4 + T-cell-mediated protective immunity has been reported Correspondence: Prof. Annette Oxenius e-mail: oxenius@micro.biol.ethz.ch for a number of viral infections [2][3][4][5]; however, the antiviral effector mechanisms exerted by CD4 + T cells in vivo have remained poorly characterized.Cytomegalovirus (CMV) is a β-herpes virus that infects a majority of the human population worldwide. After resolution of primary infection, this large DNA β-herpes virus establishes a life-long persistence in its host. CMV infection is usually clinically silent in healthy individuals. Nevertheless, CMV-infected immunosuppressed patients, such as hematopoietic BM or solid organ transplant recipients, suffer from CMV disease with potentially * These authors have contributed equally to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 2886-2895 Immunity to Infection 2887 severe clinical outcome [6]. Cellular immunity is important to control CMV infection [7,8] Results Expansion, activation, and phenotype of M25-specific CD4 + T cells during acute ...

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“…Several cells in the immune system, including NK cells, produce IL-10 early after MCMV infection. The early production of IL-10 promotes virus replication in the salivary glands by negatively affecting the maturation of DCs, leading to poor priming of T cells (26,27). We found that splenic Ly49H + and Ly49H -NK cells from the mice produced similar levels of IL-10 at day 2.5 post-MCMV infection (Fig.…”

Section: Ebi3 Promotes Il-10 Production By Nk Cells and Negatively Afmentioning

confidence: 61%

“…The serum level of IL-10 peaks at day 5 p.i. during MCMV infection (26). We found that the levels of IL-10 in sera were significantly decreased in the MCMV-infected Ebi3 −/− B6 mice (Fig.…”

Section: Ebi3 Promotes Il-10 Production By Nk Cells and Negatively Afmentioning

confidence: 67%

“…5B), indicating that the overall production of IL-10 was affected in the mice. We further examined the impact of EBI3 deficiency on DC maturation and T-cell activation, both of which are affected by IL-10 during MCMV infection (26,27). We observed higher levels of the maturation markers CD86 and CD40 on splenic DCs derived from the Ebi3 −/− B6 mice at day 5 p.i.…”

Section: Ebi3 Promotes Il-10 Production By Nk Cells and Negatively Afmentioning

confidence: 96%

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EBI3 regulates the NK cell response to mouse cytomegalovirus infection

Jensen

Chen

Folkersen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Natural killer (NK) cells are key mediators in the control of cytomegalovirus infection. Here, we show that Epstein-Barr virusinduced 3 (EBI3) is expressed by human NK cells after NKG2D or IL-12 plus IL-18 stimulation and by mouse NK cells during mouse cytomegalovirus (MCMV) infection. The induction of EBI3 protein expression in mouse NK cells is a late activation event. Thus, early activation events of NK cells, such as IFNγ production and CD69 expression, were not affected in EBI3-deficient (Ebi3 −/− ) C57BL/6 (B6) mice during MCMV infection. Furthermore, comparable levels of early viral replication in spleen and liver were observed in MCMV-infected Ebi3 −/− and wildtype (WT) B6 mice. Interestingly, the viral load in salivary glands and oral lavage was strongly decreased in the MCMV-infected Ebi3 −/− B6 mice, suggesting that EBI3 plays a role in the establishment of MCMV latency. We detected a decrease in the sustained IL-10 production by NK cells and lower serum levels of IL-10 in the MCMV-infected Ebi3 −/− B6 mice. Furthermore, we observed an increase in dendritic cell maturation markers and an increase in activated CD8 + T cells. Thus, EBI3 dampens the immune response against MCMV infection, resulting in prolonged viral persistence.natural killer cell | EBI3 | cytomegalovirus N atural killer (NK) cells play an essential role in host defense against viral infections, particularly herpesviruses, such as cytomegalovirus (CMV) (1). During infection, NK cell activation is tightly controlled by the integration of signals derived from activating and inhibitory receptors, through the interaction with target or accessory cells, and from cytokine receptors. Several activating NK receptors exist, including the activating killer cell Ig-like receptors (KIRs) in humans, the activating Ly49 receptors in rodents, NKG2D, the natural cytotoxicity receptors (i.e., NKp30, NKp44, and NKp46), and the activating Fc receptor CD16 (2). The activating receptors recognize either stress-induced ligands on viralinfected cells, virus-encoded proteins, or Ig-coated cells. Signals from the activating receptors promote cytoskeletal rearrangements and proliferation, as well as secretion of cytolytic granules and cytokines (2). The inhibitory receptors Ly49 and KIR recognize polymorphic major histocompatibility complex class I ligands that can dampen or prevent the NK cells from attacking self (2).NK cell-mediated control of viral infections has been studied extensively in mice infected with mouse CMV (MCMV). NK cells contribute directly to the early control of MCMV infection by eliminating the virus-infected cells. In C57BL/6 (B6) mice, Ly49H+ NK cells recognize MCMV-infected cells expressing the virus-encoded protein m157. This antigen-specific recognition leads to NK cell activation (3), as well as expansion and differentiation of memory NK cells (4), which is dependent on the DAP12 adapter protein, the costimulatory receptor DNAM-1, and the proinflammatory cytokine IL-12 (4-6). The DAP10 adapter protein and the cytokines IL-33 and IL-18...

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IL-10 Suppression of NK/DC Crosstalk Leads to Poor Priming of MCMV-Specific CD4 T Cells and Prolonged MCMV Persistence

Cited by 75 publications

References 45 publications

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

Adoptive transfer of cytomegalovirus‐specific effector CD4⁺T cells provides antiviral protection from murine CMV infection

EBI3 regulates the NK cell response to mouse cytomegalovirus infection

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IL-10 Suppression of NK/DC Crosstalk Leads to Poor Priming of MCMV-Specific CD4 T Cells and Prolonged MCMV Persistence

Cited by 75 publications

References 45 publications

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

Adoptive transfer of cytomegalovirus‐specific effector CD4+T cells provides antiviral protection from murine CMV infection

EBI3 regulates the NK cell response to mouse cytomegalovirus infection

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Adoptive transfer of cytomegalovirus‐specific effector CD4⁺T cells provides antiviral protection from murine CMV infection