Activating receptors promote NK cell expansion for maintenance, IL-10 production, and CD8 T cell regulation during viral infection

Abstract

Natural killer (NK) cells have the potential to deliver both direct antimicrobial effects and regulate adaptive immune responses, but NK cell yields have been reported to vary greatly during different viral infections. Activating receptors, including the Ly49H molecule recognizing mouse cytomegalovirus (MCMV), can stimulate NK cell expansion. To define Ly49H's role in supporting NK cell proliferation and maintenance under conditions of uncontrolled viral infection, experiments were performed in Ly49h−/−, perforin 1 (Prf1)−/−, and wild-type (wt) B6 mice. NK cell numbers were similar in uninfected mice, but relative to responses in MCMV-infected wt mice, NK cell yields declined in the absence of Ly49h and increased in the absence of Prf1, with high rates of proliferation and Ly49H expression on nearly all cells. The expansion was abolished in mice deficient for both Ly49h and Prf1 (Ly49h−/−Prf1−/−), and negative consequences for survival were revealed. The Ly49H-dependent protection mechanism delivered in the absence of Prf1 was a result of interleukin 10 production, by the sustained NK cells, to regulate the magnitude of CD8 T cell responses. Thus, the studies demonstrate a previously unappreciated critical role for activating receptors in keeping NK cells present during viral infection to regulate adaptive immune responses.

EBI3 regulates the NK cell response to mouse cytomegalovirus infection

“…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.…”

“…and in the serum at day 5 p.i. As reported previously, production of IL-10 early during MCMV infection is important for limiting DC maturation and T-cell activation to prevent harmful immune-mediated tissue damage in the host (26,27). During MCMV infection, IL-10 production by NK cells and other immune cells can suppress the maturation DCs, leading to poor priming of CD4 + T cells (26).…”

“…During MCMV infection, IL-10 production by NK cells and other immune cells can suppress the maturation DCs, leading to poor priming of CD4 + T cells (26). Furthermore, NK cell-mediated IL-10 production during MCMV infection regulates CD8 + T-cell activation, where a blockade of IL-10 increases the CD8 + T-cell response against MCMV (27). We detected an increase in both the maturation markers of DCs and the percentage of activated CD8 + T cells in the MCMV-infected EBI3-deficient mice, indicating that the observed decrease in IL-10 production in the EBI3-deficient mice was able to enhance the subsequent T-cell response.…”

“…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.…”

Les cellulesnatural killer

“…Des résultats similaires ont également été obtenus dans un modèle de vaccination utilisant de l'ovalbumine en présence d'un adjuvant [24]. Il a été également démontré, dans des souris déficientes pour la perforine, que les cellules NK Ly49H + peuvent directement supprimer la réponse des lymphocytes T CD8 anti-MCMV en sécrétant de l'IL-10 [25] (Figure 4B). En résumé, toutes ces études ont montré que l'activation des cellules NK a un impact sur l'immunité cellulaire T. Ces travaux suggèrent que par leur action sur (1) la charge antigénique, (2) la quantité et la fonctionnalité des cellules dendritiques conventionnelles, et (3) le niveau des cytokines inflammatoires, les cellules NK influencent positivement ou négativement l'activation des lymphocytes T. Alors que la cytotoxicité des cellules NK contribue largement aux défenses antivirales, on peut s'interroger sur l'avantage biologique qu'il y a à limiter les réponses adaptatives.…”