Inflammasomes cross-talk with lymphocytes to connect the innate and adaptive immune response

Abstract

Background: Innate and adaptive immunity are two different parts of the immune system that have different characteristics and work together to provide immune protection. Inflammasomes are a major part of the innate immune system that are expressed widely in myeloid cells and are responsible for inflammatory responses. Recent studies have shown that inflammasomes are also expressed and activated in lymphocytes, especially in T and B cells, to regulate the adaptive immune response. Activation of inflammasomes is also under the control of lymphocytes. Therefore, we propose that inflammasomes act as a bridge and they provide crosstalk between the innate and adaptive immune systems to obtain a fine balance in immune responses.

Aim of review: This review systematially summarizes the interaction between inflammasomes and lymphocytes and describes the crosstalk between the innate and adaptive immune systems induced by inflammasomes, with the aim of providing new directions and important areas for further research.

Key scientific concepts of review: When considering the novel function of inflammasomes in various lymphocytes, attention should be given to the activity of specific inflammasomes in studies of lymphocyte function. Moreover, research on the function of various inflammasomes in lymphocytes will help advance knowledge on the mechanisms and treatment of various diseases, including autoimmune diseases and tumors. In addition, when studying inflammatory responses, inflammasomes in both lymphocytes and myeloid cells need to be considered.

Keywords: AIM2; Adaptive immunity; Inflammasome; Innate immunity; Lymphocyte; NLRP3.

Fig. 1

NLRP3 inflammasome in CD4⁺ T lymphocytes.Expression of NLRP3 inflammasmes in T lymphocytes: ①TCR signal alone or together with CD46 signal to induce IL-2 secretion. ②IL-2 activates STAT5 by interacting with IL-2R in an autocrine manner, and then STAT5 is translocated into nucleus to bind NLRP3 promoter and promote NLRP3 expression. Activation of NLRP3 inflammasmes in T lymphocytes:③Nigericin induces K⁺ efflux and activates NLRP3 inflammaosme. ④Cadmium induces mtROS to activation NLRP3 inflammsome. ⑤CD46 activates C5 and cleaves C5 into C5a, and then C5a binds C5aR1 and induces ROS to activate NLRP3 inflammmsome. ⑥Activated NLRP3 inflammasome secretes mature IL-1β and IL-18 through GSDMS pores. Function of NLRP3 inflammasmes in T lymphocytes: On the one hand, NLRP3 translocates into nucleus and acts as a transcription regulator in Th2 and Treg cells. On the other hand, NLRP3 inflammasome activity of CD4⁺ T lymphocytes is pivotal for Th1/Th17 balance. Besides, NLRP3 inflammasomes in CD4⁺ T cells involve in many diseases.

Fig. 2

NLRP3 inflammasome in B-lymphocytes. ①BAFF interacts with BAFFR and recruits TRAF3 which activates NF-κB and promotes the expression of NLRP3 and pro-IL-1β.②TRAF3 induces cIAP–TRAF2 which interacts directly with NLRP3 and promotes NLRP3 inflammasome activation.③BAFF interacts with BAFFR and recruits Src, Src induces mtROS to activate NLRP3 inflammmsome. ④Src induces K⁺ efflux to activate NLRP3 inflammmsome. ⑤Canonical PAMPs including LPS and β-glucan activate NLRP3 inflammsome. ⑥Activated NLRP3 inflammasomes in B cells promote the production of IgM, up-regulation of PD-L1, and maturation and secretion of IL-1β and IL-18.

Fig. 3

AIM2 inflammasome in T lymphocytes. A. ①IL-21 interacts with IL-21R and activates TET2 to promote AIM2 expression in Tfh cells.②TCR activation induces AIM2 expression. ③TGF-β interacts with TGF-βR and promotes AIM2 expression in Treg cells. ④AIM2 interacts with the RACK1/PP2Acomplex to regulate Akt phosphorylation, maintain Treg homeostasis during inflammation. ⑤AIM2 senses dsDNA and is assembled into inflammasomes in T cells. ⑥AIM2 binds directly to C-Maf and STAT3 to regulate the expression of IL-21, CXCR5, and PD-1 in Tfh cells. B.① IFN-γ interacts with IFN-γR and promotes AIM2 expression in B cells.②AIM2 in B cells can act as a transcription regulator, such as regulating the expression of Bmp11, CXCL9, CCL6, and CXCL16.③AIM2 senses dsDNA and is assembled into inflammasomes in B cells.

Fig. 4

Innate and adaptive immune system crosstalk through inflammasome. A.The innate immune system regulates the adaptive immune response through inflammasomes: ①CD4⁺ T cells produce cytokines including IL-10, IFN-γ, and TGF-β to inhibit inflammasomes activation in innate immune cells, and also produce cytokines like IL-17 to activate inflammasomes in innate immune cells.②CD8⁺ T cells derived IFN-γ cooperate with the PD-1/PD-L1 pathway to activate NLRP3 inflammasomes, and CD8⁺ T cells secrets perforin to induce potassium efflux and calcium influx to activate inflammasomes in innate immune cells.③B cells secret antibodies and interact with kinds of receptors including TLR4, CD36, and FcγR to regulate inflammasomes in innate immune cells. B.The adaptive immune system targets inflammasomes to regulate the innate immune response: ④Activation of both canonical and non-canonical inflammasomes in the innate immune system promotes NETs formation, which then regulate adaptive immunity of B and T cells. ⑤Innate immune cells derived proinflammatory cytokines including IL-1β and IL-18 effect the function of various lymphocytes. ⑥Inflammasomes inhibit IFN-I, which broadly regulates lymphocytes of the adaptive immune system, and is produced by innate immune cells to regulate lymphocyte function