NLRC3 negatively regulates CD4+ T cells and impacts protective immunity during Mycobacterium tuberculosis infection

Shengfeng Hu; Xialin Du; Yulan Huang; Yuling Fu; Yalong Yang; Xiaoxia Zhan; Wenting He; Qian Wen; Xinying Zhou; Chaoying Zhou; Xiao-Ping Zhong; Jiahui Yang; Wenjing Xiong; Ruining Wang; Yuchi Gao; Li Ma

doi:10.1371/journal.ppat.1007266

NLRC3 negatively regulates CD4+ T cells and impacts protective immunity during Mycobacterium tuberculosis infection

PLoS Pathog. 2018 Aug 22;14(8):e1007266. doi: 10.1371/journal.ppat.1007266. eCollection 2018 Aug.

Authors

Shengfeng Hu¹, Xialin Du¹, Yulan Huang¹, Yuling Fu¹, Yalong Yang¹, Xiaoxia Zhan², Wenting He¹, Qian Wen¹, Xinying Zhou¹, Chaoying Zhou¹, Xiao-Ping Zhong^{1

3}, Jiahui Yang¹, Wenjing Xiong¹, Ruining Wang¹, Yuchi Gao¹, Li Ma¹

Affiliations

¹ Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.
² Department of laboratory medicine, The first Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
³ Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, NC, United States of America.

Abstract

NLRC3, a member of the NLR family, has been reported as a negative regulator of inflammatory signaling pathways in innate immune cells. However, the direct role of NLRC3 in modulation of CD4+ T-cell responses in infectious diseases has not been studied. In the present study, we showed that NLRC3 plays an intrinsic role by suppressing the CD4+ T cell phenotype in lung and spleen, including differentiation, activation, and proliferation. NLRC3 deficiency in CD4+ T cells enhanced the protective immune response against Mycobacterium tuberculosis infection. Finally, we demonstrated that NLRC3 deficiency promoted the activation, proliferation, and cytokine production of CD4+ T cells via negatively regulating the NF-κB and MEK-ERK signaling pathways. This study reveals a critical role of NLRC3 as a direct regulator of the adaptive immune response and its protective effects on immunity during M. tuberculosis infection. Our findings also suggested that NLRC3 serves as a potential target for therapeutic intervention against tuberculosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD4 Lymphocyte Count
CD4-Positive T-Lymphocytes / pathology*
CD4-Positive T-Lymphocytes / physiology
Cells, Cultured
Down-Regulation / genetics
Down-Regulation / immunology
Female
Immunity / genetics*
Intercellular Signaling Peptides and Proteins / physiology*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mycobacterium tuberculosis / immunology*
Tuberculosis / genetics
Tuberculosis / immunology*
Tuberculosis / pathology

Substances

Intercellular Signaling Peptides and Proteins
NLRC3 protein, mouse

Grants and funding

National Science and Technology Key Projects on Major Infectious Diseases (2017ZX10201301-008 LM), National Natural Science Foundation of China (81772150, 81571951, LM) and National Natural Science Foundation of China (81641062, SH) played role in the study design; Natural Science Foundation of Guangdong Province (2016A030311001, LM) and Natural Science Foundation of Guangdong Province (2017A030310268, SH), Science and Technology Project of Guangdong Province (2017A020212007, LM), Science and Technology Project of Guangzhou (201707010215, LM) and Medical Scientific Research Foundation of Guangdong Province (A2017073, SH) played role in data collection and analysis.