Objective NLRP3 inflammasome regulates T cell responses. This study examined the roles of NLRP3 inflammasome activation in the regulation of T follicular helper (Tfh) cells during humoral response to T dependent antigens and in systemic lupus erythematosus (SLE).
Methods NLRP3 inflammasome activation of Tfh cells was studied in B6, MRL/lpr and NZM2328 mice and in SLE patients and healthy controls using a fluorescence-labelled caspase-1 inhibitor probe. MCC950, a selective inhibitor of NLRP3, was used to investigate the relation between NLRP3 inflammasome activation and germinal centre (GC) reaction, Ab responses to immunisation, and autoantibody production.
Results NLRP3 inflammasome activation in Tfh cells after immunisation was identified in B6 mice. MCC950 inhibited humoral responses to sheep red blood cell and NP-CGG with reduction of the GC reaction. B6 mice with lymphoid cell-specific deletion of NLRP3 or Casp1 mounted suboptimal humoral responses with impaired GC formation and defective affinity maturation. In MRL/lpr and NZM2328 mice, inhibition of NLRP3 activation suppressed NLRP3 activated Tfh cell expansion as well as attenuated lupus-like phenotypes. Tfh cells with activated NLRP3 inflammasome exhibited increased expression of molecules for Tfh cell function and differentiation, and had greater ability to activate B cells. In SLE patients, disease activity was positively correlated with an increase in the activated NLRP3+ Tfh population and this population was markedly reduced in response to therapy.
Conclusions The activation of NLRP3 inflammasome in Tfh cells is an integral part of responses to immunisation. The activated NLRP3+ Tfh population is essential for optimal humoral responses, GC formation and autoimmunity.
- Lupus Erythematosus, Systemic
- T-Lymphocyte subsets
Data availability statement
All data relevant to the study are included in the article. Not applicable.
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Handling editor Josef S Smolen
ZZ and BX contributed equally.
Contributors ZZ, BX, S-SJS, NY and SMF designed the research. All authors were involved in acquisition, analysis and interpretations of the data as well as preparing the manuscript. NY and SMF had full access to all the data and are responsible for the integrity of the data and accuracy of the data analysis. SMF is the guarantor who accepts full responsibility for the work and conduct of the studies and controlled the decision to publish.
Funding This work was supported in part by the National Natural Science Foundation of China (81701595, 81671593，81971519 and 82171770) and Guangdong Natural Science Foundation (2021A1515012072). SMF was supported in part by NIH grants (R01 AR-047988 and R01 AI-148231) and a grant from the Alliance for Lupus Research (TIL332635).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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