NK cells modulate the lung dendritic cell‐mediated Th1/Th17 immunity during intracellular bacterial infection

Abstract

The impact of the interaction between NK cells and lung dendritic cells (LDCs) on the outcome of respiratory infections is poorly understood. In this study, we investigated the effect and mechanism of NK cells on the function of LDCs during intracellular bacterial lung infection of Chlamydia muridarum in mice. We found that the naive mice receiving LDCs from C. muridarum-infected NK-cell-depleted mice (NK-LDCs) showed more serious body weight loss, bacterial burden, and pathology upon chlamydial challenge when compared with the recipients of LDCs from infected sham-treated mice (NK+LDCs). Cytokine analysis of the local tissues of the former compared with the latter exhibited lower levels of Th1 (IFN-γ) and Th17 (IL-17), but higher levels of Th2 (IL-4), cytokines. Consistently, NK-LDCs were less efficient in directing C. muridarum-specific Th1 and Th17 responses than NK+LDCs when cocultured with CD4 + T cells. In NK cell/LDC coculture experiments, the blockade of NKG2D receptor reduced the production of IL-12p70, IL-6, and IL-23 by LDCs. The neutralization of IFN-γ in the culture decreased the production of IL-12p70 by LDCs, whereas the blockade of TNF-α resulted in diminished IL-6 production. Our findings demonstrate that NK cells modulate LDC function to elicit Th1/Th17 immunity during intracellular bacterial infection.Keywords: Chlamydia muridarum r Lung dendritic cells r Natural killer cells r NKG2D r Th1/Th17 cells Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionChlamydia is an obligate intracellular bacterial pathogen that afflicts humans with a variety of diseases, posing a menace to public health worldwide [1]. Clinically significant chlamydial species are C. trachomatis and C. pneumoniae that cause various diseases such as trachoma, pneumonia, and sexually transmitted Correspondence: Prof. Xi Yang e-mail: yangxi@cc.umanitoba.ca diseases, and are also associated with chronic inflammatory diseases [1,2]. Thus far there is no vaccine to prevent chlamydial diseases in humans. Rising public health concerns with chlamydial diseases underscores the development of an effective vaccine; however, limited understanding of the immunobiology of chlamydial infections is the main constraint in achieving this goal [3]. In recent years, significant advances have been made in this field using mouse infection model of C. muridarum, the mouse biovar of C. trachomatis [4]. Accumulating evidence indicates that the induction of Th1 responses, particularly IFN-γ production, is a key to protective immunity against chlamydial lung infections [4].C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 2810-2820 Immunity to infection 2811Initial studies have further acknowledged that Th17 responses are also protective in chlamydial lung infections [5][6][7], and that both Th1 and Th17 responses act in synergy to generate the protective immunity [8][9][10]. In contrast, Th2 responses characterized by IL-4 production a...

Intranasal Immunization with the Commensal Streptococcus mitis Confers Protective Immunity against Pneumococcal Lung Infection

“…Moreover, Th17 immunity was significantly increased in the lungs, but not the spleen, suggesting local protective immunity induced by S. mitis. Emerging evidence also points out the importance of local mucosal immunity in providing defense against respiratory infections (43,44). Taken together, our data shed light on the impact of mucosal immunization of mice with S. mitis on local T cell-mediated immunity against pneumococci.…”

“…Isolation of cells from lungs and spleen. The lungs and spleen were removed from the euthanized mice and processed into single᎑cell suspensions, as described previously (43). In brief, the lungs were digested in 10 mg/ml collagenase XI (Sigma-Aldrich, Israel) in RPMI 1640 (Sigma-Aldrich, United Kingdom) for 1 hour at 37°C.…”

NK-DC Crosstalk in Immunity to Microbial Infection

“…Furthermore, cytokine analysis of the local tissues of the recipient mice receiving NK-DC compared with those receiving NK+DC exhibited lower levels of Th1 (IFN- γ ) and Th17 (IL-17) but higher levels of Th2 (IL-4) cytokines. Consistently, NK-DCs were less efficient in directing Chlamydiae -specific Th1 and Th17 responses than NK+DCs when co-cultured with CD4 + T cells [56]. These studies taken together demonstrate that NK cells modulate DC function to elicit Th1/Th17 immunity during intracellular bacterial infection (Figure 1).…”

“…Our laboratory has studied the modulating effect of NK cells on the function of DCs using an in vivo model of chlamydial lung infection [55, 56]. Chlamydia is an obligate intracellular bacterium causing various human diseases.…”

Natural killer cells in host defense against veterinary pathogens

“…It however remains unclear whether NK cells in turn modulate DCs to influence the adaptive immune responses. In mouse models of bacterial infection, NK cells have been reported to confer protective T cell immunity, characterized by IFN-␥ and IL-17 production, by modulating the function of DCs (Shekhar et al, 2015). It would be interesting to assess the impact of NK cells on DC function in mounting adaptive immunity to infections in different domestic animals.…”