IL-10 Restricts Activation-Induced Death of NK Cells during Acute Murine Cytomegalovirus Infection

Abstract

Interleukin-10 (IL-10) is an immunomodulatory cytokine that acts to antagonize T cell responses elicited during acute and chronic infections. The IL-10 receptor (IL-10R) signalling pathway thus provides a potential therapeutic target in strategies aimed at combating infectious diseases. In this study, we set out to investigate whether IL-10 expression impacted on Natural Killer (NK) cells. Murine cytomegalovirus (MCMV) infection provides the best characterized in vivo system to evaluate the NK cell response, with NK cells being critical in the early control of acute infection. Blockade of IL-10 receptor (IL-10R) during acute MCMV infection markedly reduced the accumulation of cytotoxic NK cells in the spleen and lung; a phenotype associated with a transient elevation of virus DNA load. Impaired NK cell responsiveness after IL-10R blockade was attributed to elevated levels of apoptosis observed in NK cells exhibiting an activated phenotype. We therefore conclude that IL-10 contributes to antiviral innate immunity during acute infection by restricting activation-induced death in NK cells.

Neutrophils Recruited by IL-22 in Peripheral Tissues Function as TRAIL-Dependent Antiviral Effectors against MCMV

“…Of note, NK depletion did not influence neutrophil accumulation in infected tissues (data not shown). Taken with the observations that T cells secrete IL-22 (Figures 2A–2C) and that MCMV replication (which is elevated after NK1.1 depletion in this model [Stacey et al., 2011]) directly induces CXCL1 production (Figure 3J), these results demonstrate that NK1.1 − cells are capable of promoting neutrophil recruitment in the absence of NK cells. Importantly, these results also imply that neutrophil activation of NK cells is not the primary mechanism through which neutrophils control MCMV.…”

Tumor-priming converts NK cells to memory-like NK cells

“…4B). In line with previously published data 27 and with the notion that high expression of the activation marker CD25 is per se associated with increased AnnexinV binding, 28 we attribute the extensive rate of apoptosis in CIML-NK cells to the induction of an IL12-mediated "activationinduced cell death" (AICD). As a result of this apparently shifted cell balance between proliferation and apoptosis the total cell number of TIML-NK cells was upregulated (d3: fold increase 1.53 § 0.47, proliferation >> apoptosis) but virtually unchanged in CIML-NK cells (d3: fold increase 1.0 § 0.25, proliferation D apoptosis) (Fig.…”

Cytomegalovirus-Specific IL-10-Producing CD4+ T Cells Are Governed by Type-I IFN-Induced IL-27 and Promote Virus Persistence

“…Leukocytes were extracted from murine spleen, salivary glands and lungs as described previously [13,60]. For CD4 + functional responses, isolated leukocytes were stimulated for 2 hours with 3 μg/ml m09, (GYLYIYPSAGNSFDL), M25 (NHLYETPISATAMVI), m139 (TRPYRYPRVCDASLS), and m142 (RSRYLTAAAVTAVLQ) MCMV MHCII peptides (Genscript).…”

“…Data obtained from the MCMV model has demonstrated an important protective role for cellular IL-10 during acute CMV infection. Myeloid cells and B cells are the predominant sources of IL-10 during initial MCMV infection [13,14]. IL-10 limits virus induced weight loss, pro-inflammatory cytokine production and activation-induced NK cell death [13–15].…”

“…Myeloid cells and B cells are the predominant sources of IL-10 during initial MCMV infection [13,14]. IL-10 limits virus induced weight loss, pro-inflammatory cytokine production and activation-induced NK cell death [13–15]. Sustained acute MCMV replication in situations of high virus load also induces IL-10 production by NK cells that restricts CD8 + T cell-mediated immune pathology [16].…”