Human TH17 cells engage gasdermin E pores to release IL-1α on NLRP3 inflammasome activation

Abstract

It has been shown that innate immune responses can adopt adaptive properties such as memory. Whether T cells utilize innate immune signaling pathways to diversify their repertoire of effector functions is unknown. Gasdermin E (GSDME) is a membrane pore-forming molecule that has been shown to execute pyroptotic cell death and thus to serve as a potential cancer checkpoint. In the present study, we show that human T cells express GSDME and, surprisingly, that this expression is associated with durable viability and repurposed for the release of the alarmin interleukin (IL)-1α. This property was restricted to a subset of human helper type 17 T cells with specificity for Candida albicans and regulated by a T cell-intrinsic NLRP3 inflammasome, and its engagement of a proteolytic cascade of successive caspase-8, caspase-3 and GSDME cleavage after T cell receptor stimulation and calcium-licensed calpain maturation of the pro-IL-1α form. Our results indicate that GSDME pore formation in T cells is a mechanism of unconventional cytokine release. This finding diversifies our understanding of the functional repertoire and mechanistic equipment of T cells and has implications for antifungal immunity.

Real-time fluorescence imaging flow cytometry enabled by motion deblurring and deep learning algorithms

“…[1][2][3] This innovative technology combines the advantages of flow cytometry and fluorescence microscopy, enabling the acquisition of highresolution cell images with high throughput in a continuous flow mode. 4 The versatility of IFC has been demonstrated in a number of biological and medical fields, such as pathology, [5][6][7][8] immunology, [9][10][11] microbiology, [12][13][14] cancer treatment, [15][16][17][18] and molecular biology. [19][20][21][22] Real-time cell classification is a critical function of IFC, particularly for larger-scale single-cell sorting and analysis.…”

Plasmodium falciparum adapts its investment into replication versus transmission according to the host environment

“…F1 consists of a mixture of inflammatory markers that support effector Th1/Th2/Th9/Th17 responses (i.e. hyperinflammatory state), F2 represents a Th2 response, F3 represents markers that support follicular helper T cell development and Th17 ( Dong, 2021 ; Chao et al, 2023 ), F4 represents markers of immune paralysis/tissue-injury linked to response to cellular/tissue injury ( Kumar et al, 2014 ), and F5 represents the inflammasome/Th1 response ( Weiss et al, 2018 ). F4 showed a significant positive association with ap2-g and Pfsir2a transcription and fever ( Figure 3C ).…”

The CARD8 inflammasome drives CD4+T-cell depletion in HIV-1 infection

“…For example, IFI16 and NLRP3 have been implicated in HIV-1-induced CD4 + T cell pyroptosis 25,26 , but these two inflammasomes are only functional in certain subsets of CD4 + T cells and their ability to drive pyroptosis of human T cells has not been validated 27,28 .…”

“…However, the lack of complete protection of CD4 + T cells in the CARD8 -deficient immune system could also be attributed to the activation of other inflammasome sensors by HIV-1. For example, IFI16 and NLRP3 have been implicated in HIV-1-induced CD4 + T cell pyroptosis 25,26 , but these two inflammasomes are only functional in certain subsets of CD4 + T cells and their ability to drive pyroptosis of human T cells has not been validated 27,28 . Although the function of various components of inflammasomes has been studied in T cells, the CARD8 inflammasome is best characterized to trigger pyroptosis in human lymphocytes 29 .…”