CD69 Deficiency Enhances the Host Response to Vaccinia Virus Infection through Altered NK Cell Homeostasis

Abstract

During the host response to viral infection, the transmembrane CD69 protein is highly upregulated in all immune cells. We have studied the role of CD69 in the murine immune response to vaccinia virus (VACV) infection, and we report that the absence of CD69 enhances protection against VACV at both short and long times postinfection in immunocompetent and immunodeficient mice. Natural killer (NK) cells were implicated in the increased infection control, since the differences were greatly diminished when NK cells were depleted. This role of NK cells was not based on an altered NK cell reactivity, since CD69 did not affect the NK cell activation threshold in response to major histocompatibility complex class I NK cell targets or protein kinase C activation. Instead, NK cell numbers were increased in the spleen and peritoneum of CD69-deficient infected mice. That was not just secondary to better infection control in CD69-deficient mice, since NK cell numbers in the spleens and the blood of uninfected CD69 ؊/؊ mice were already augmented. CD69-deficient NK cells from infected mice did not have an altered proliferation capacity. However, a lower spontaneous cell death rate was observed for CD69 ؊/؊ lymphocytes. Thus, our results suggest that CD69 limits the innate immune response to VACV infection at least in part through cell homeostatic survival. IMPORTANCEWe show that increased natural killer (NK) cell numbers augment the host response and survival after infection with vaccinia virus. This phenotype is found in the absence of CD69 in immunocompetent and immunodeficient hosts. As part of the innate immune system, NK lymphocytes are activated and participate in the defense against infection. Several studies have focused on the contribution of NK cells to protection against infection with vaccinia virus. In this study, it was demonstrated that the augmented early NK cell response in the absence of CD69 is responsible for the increased protection seen during infection with vaccinia virus even at late times of infection. This work indicates that the CD69 molecule may be a target of therapy to augment the response to poxvirus infection. V accinia virus (VACV) is a member of the Poxviridae family and was used as a vaccine to eradicate the variola virus, which is from the same family. Since then, it has commonly been used in research as a vaccine vector model. It is a large DNA virus with a linear double-stranded DNA genome that encodes Ͻ200 proteins (1). It has a broad cellular tropism and infects almost any cell line in culture. Members of this virus family do not usually establish persistent or latent infections and have a low mutation rate (2). VACV infection is initially controlled by the innate immune response, but it can be eradicated only by adaptive immunity, and Rag Ϫ/Ϫ mice finally succumb to the infection (3). Natural killer (NK) cells are crucial players in the first line of defense against viral infections. Through their expression of a range of germ line-encoded receptors, they are able to recognize v...

Comparative Analysis of Conventional Natural Killer Cell Responses to Acute Infection with Toxoplasma gondii Strains of Different Virulence

“…In contrast, after cps1-1 infection, only mature CD11b+ cNK cells expressed KLRG1. In spleen, the frequency of CD69+ cNK cells was higher on those from RH- and ME49-infected animals compared with cps1-1 , which may indicate higher level of activation-induced cell death ( 39 , 44 ) and explain the loss of the mature cNK cell population in RH and ME49 infections. In both PEC and spleen, the highest parasite burdens were detected after infection with RH strain, followed by ME49 strain.…”

“…CD69 is upregulated on activated cNK cells and is an indicator of their migratory capacity ( 36 , 37 ). CD69 expression has also been shown to have a regulatory function for cNK cells ( 38 , 39 ). To further define how cNK cells respond to T. gondii infection and to compare how different parasite strains affect cNK cell activation and migration, we measured CD69 expression on cNK cells directly ex vivo without restimulation.…”

CD69 Plays a Beneficial Role in Ischemic Stroke by Dampening Endothelial Activation

“…11 In contrast, CD69-deficient mice were found to have less inflammation in models of dextran sulfate sodium-induced acute and chronic colitis, 12 cigarette smoke-induced pulmonary inflammation, 13 bleomycininduced lung inflammation and fibrosis, 14 another study of collagen-induced arthritis, 15 and allergic airway inflammation, 16 and they were also protected from vaccinia virus infection. 17 These results suggest that the role of CD69 depends on the type of disease and the cell types involved, and it may also depend on the strain of CD69-deficient mice used. 5 The first aim of this study was to investigate whether CD69 was involved in stroke outcome, and we examined this in both transient and permanent cerebral ischemia.…”

“…18 CD69 -/mice had been backcrossed on the C57BL/6 and the BALB/c backgrounds at least nine times. 17 Unless otherwise stated, the studies were performed in mice on the C57BL/6 background. Animal work was conducted with approval of the ethical committee of the University of Barcelona (CEEA) in compliance with the local regulations, the Spanish legislation (Real Decreto 53/2013), and the European Community Directives, and it is reported following the ARRIVE guidelines.…”

Zika virus infection preferentially counterbalances human peripheral monocyte and/or NK-cell activity

“…Moreover, NK cells behave differently ex vivo and in vivo (49), which may explain the different levels of CD69 detected in patients and in ex vivo ZIKV-infected NK cells. It was also reported in CD69-deficient mice that the activity of NK cells remains functional (50). High levels of key NK activation markers, including the degranulation marker CD107a and intracellular cytokine IFN γ indicate the higher activation status of NK cells.…”