RESEARCH ARTICLE
NK cells inhibit anti‐Mycobacterium bovis BCG T cell responses
and aggravate pulmonary inflammation in a direct lung infection
mouse model
Dongfang Wang
1,2
|
Xiuling Gu
1,2
|
Xiaoman Liu
1
|
Songtao Wei
1
|
Bin Wang
1,2
|
Min Fang
1,3
1
CAS Key Laboratory of Pathogenic
Microbiology and Immunology, Institute of
Microbiology, Chinese Academy of Sciences,
Beijing, China
2
University of Chinese Academy of Sciences,
Beijing, China
3
International College, University of Chinese
Academy of Sciences, Beijing, China
Correspondence
Dr. Min Fang, CAS Key Laboratory of
Pathogenic Microbiology and Immunology,
Institute of Microbiology, Chinese Academy of
Sciences, Beijing 100101, China.
Email: fangm@im.ac.cn
Funding information
National Thousand Talent Plan of China;
National Natural Science Foundation of China,
Grant/Award Numbers: 31322020 and
31370877
Abstract
Tuberculosis remains a threat to public health. The major problem for curing this disease is latent
infection, of which the underlying mechanisms are still not fully understood. Previous studies
indicate that natural killer (NK) cells do not play a role in inhibiting the growth of Mycobacterium
tuberculosis in the lung, and recent studies have revealed that NK cells regulate the adaptive
immunity during mycobacterial infection. By using a mouse model of direct lung infection with
Mycobacterium bovis bacillus Calmette‐Guerin (BCG), we found that the presence of NK cells
postponed the priming and activation of T cells after BCG infection. In addition, depletion of
NK cells before infection alleviated pulmonary pathology. Further studies showed that NK cells
lysed BCG‐infected macrophages in an NKG2D dependent manner. Thus, NK cells did not play
a direct role in control BCG, but aggravated the pulmonary inflammation and impaired anti‐
BCG T cell immunity, likely through killing BCG‐infected macrophages. Our results may have
important implications for the design of immune therapy to treat tuberculosis.
KEYWORDS
BCG, NK cells, NKG2D, pulmonary pathology, T cell responses
1
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INTRODUCTION
Tuberculosis is an ancient infectious disease caused by Mycobacterium
tuberculosis (Mtb). It is estimated that about one third of the world's pop-
ulation is latently infected with Mtb (O'Garra et al., 2013). Mycobacteria
contain unique mycolic acid in the cell wall, which enable the bacteria to
resist drugs and cytolysis of macrophages. Moreover, by actively secret-
ing virulent factors that can interfere with host immune system, Mtb
evades being cleared and establishes latent infection (Brodin,
Rosenkrands, Andersen, Cole, & Brosch, 2004). In chronic latent infec-
tion state, the immune responses prevent bacterial dissemination but
are not vigorous enough to clear the bacteria (Culley, 2009). Mycobacte-
rium bovis bacillus Calmette‐Guerin (BCG) is an attenuated strain of
Mycobacterium and has been used as the only licensed vaccine against
tuberculosis for nearly a century (Hayashi et al., 2009).
Orchestration of the host immune responses to Mtb results in the
formation of granuloma, which is the typical pulmonary pathology of
tuberculosis in human (O'Garra et al., 2013). The formation of granu-
loma can be regarded as a balance between the mycobacteria and
the immune system, which is crucial in latent infection of Mtb (Russell,
Cardona, Kim, Allain, & Altare, 2009). Most mouse models cannot reca-
pitulate the formation of granuloma in the lung after Mtb infection,
making it difficult to study the mechanisms of Mtb latent infection
(Cyktor et al., 2013). However, the use of inbred mice with depletion
of certain genes or cells reveals that immune factors, such as IL‐12,
IFN‐γ, ΤΝF‐α, and CD4
+
T cells, are critical in controlling Mtb infection
in mouse. The importance of these factors in human has been validated
by clinical studies (O'Garra et al., 2013).
Natural killer (NK) cells are an important component of the innate
immune system for defence against tumour and infectious pathogens
such as virus and bacteria. Direct killing of infected host cells by NK
cells plays an important role in controlling the invading pathogens
(Wang, Ma, Wang, Liu, & Fang, 2013). Previous studies have shown
that NK cells produce IFN‐γ and IL‐22 after Mtb infection, enhancing
the cytolysis of macrophages and promoting the function of CD4
+
T
cells (Dhiman et al., 2009; Flynn et al., 1993). Human NK cells also pro-
duced IFN‐γ when exposed to BCG (Portevin & Young, 2013). Deple-
tion of NK cells before Mtb infection did not affect the bacteria load in
Received: 28 September 2017 Revised: 22 January 2018 Accepted: 7 February 2018
DOI: 10.1111/cmi.12833
Cellular Microbiology. 2018;20:e12833.
https://doi.org/10.1111/cmi.12833
© 2018 John Wiley & Sons Ltdwileyonlinelibrary.com/journal/cmi 1of12
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