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

Date Published: August 22, 2018

Publisher: Public Library of Science

Author(s): 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, David M. Lewinsohn.

http://doi.org/10.1371/journal.ppat.1007266

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.

Partial Text

Nucleotide-binding oligomerization domain-like receptors (NLRs) belong to a large family of cytoplasmic sensors that act in response to host perturbation by infectious agents or cellular stress [1,2]. NLRs participate in a very diverse range of biological functions by regulating innate and acquired immune responses, and thus, contribute to immunity against infectious diseases. Some NLRs, such as NLRP3, NLRP7, and NLRC4, have been reported to promote the production of the proinflammatory cytokines, pro-IL-1β and pro-IL-18, via inflammasomes [3–5]. Other NLRs, such as NOD1, NOD2, NLRC5, and CIITA, are known to activate nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPKs), and interferon (IFN) regulatory factors (IRFs) to stimulate innate immunity [6,7]. On the contrary, NLRP4, NLRP6, NLRP12, and NLRX1 have been demonstrated as negative regulators of inflammation [8–10]. In recent years, the roles of NLRs in regulating T cell responses have increasingly received research attention. Surprisingly, NLRP12 was found to act as a vital negative regulator of T-cell-mediated immunity and to influence NF-κB regulation and IL-4 production [11]. NOD1 and NOD2 promote the positive maturation of CD8 single-positive thymocytes in a thymocyte-intrinsic manner [12]. NLRP3 expression in CD4+ T cells was found to be required for completion of the inflammasome-mediated differentiation of T helper type 1 (Th1) and Th2 cells [13,14]. However, the exact roles of various NLR family members in regulating adaptive immune responses remain unclear.

Accumulating evidence that NLRs play an intrinsic role in regulating T cell responses lymphoid tissues [11,13]. However, to our known, contribution for NLRs modulation of T-cell responses directly in infectious diseases has not been studied. In the present study, we focused on elucidating the roles of NLRC3 in shaping CD4+ T cell responses in vivo and in vitro, in particular during M. tuberculosis infection. We found that NLRC3 played an intrinsic role in regulating negatively CD4+ T cell responses in lungs and lymphoid tissues, including differentiation and proliferation, which in turn suppresses the innate immune responses and promotes M. tuberculosis survival.

 

Source:

http://doi.org/10.1371/journal.ppat.1007266

 

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