Transcriptional profiling identifies caspase-1 as a T cell–intrinsic regulator of Th17 differentiation

Abstract

Dendritic cells (DCs) are critical for the differentiation of pathogen-specific CD4 T cells. However, to what extent innate cues from DCs dictate transcriptional changes in T cells remains elusive. Here, we used DCs stimulated with specific pathogens to prime CD4 T cells in vitro and found that these T cells express unique transcriptional profiles dictated by the nature of the priming pathogen. More specifically, the transcriptome of in vitro C. rodentium–primed Th17 cells resembled that of Th17 cells primed following infection in vivo but was remarkably distinct from cytokine-polarized Th17 cells. We identified caspase-1 as a unique gene up-regulated only in pathogen-primed Th17 cells and discovered a critical role for T cell–intrinsic caspase-1, independent of inflammasome, in optimal priming of Th17 responses. T cells lacking caspase-1 failed to induce colitis or confer protection against C. rodentium infection due to suboptimal Th17 cell differentiation in vivo. This study underlines the importance of DC-mediated priming in identifying novel regulators of T cell differentiation.

CARD8 inflammasome activation triggers pyroptosis in human T cells

“…To this end, it has been shown that NLRP3 functions as a transcriptional regulator of Th2 differentiation as evidenced in a loss‐of‐function (Bruchard et al , ) or gain‐of‐function setting (Braga et al , ). Adding to this, a recent study suggests that caspase‐1 plays a critical role in Th17 differentiation, independent of its catalytic activity (Gao et al , ). While it is difficult to reconcile these different studies into a plausible working model, it has to be considered that differences in cell type, ligands, species, and experimental readouts may account for these results.…”

Suppression of Inflammasome Activation by IRF8 and IRF4 in cDCs Is Critical for T Cell Priming

“…These three signals are necessary to activate and prime antigen-specific T cells, a process that can take several days to complete (Inaba et al, 2000;Jain and Pasare, 2017). On the basis of the initial PRRs engaged by a pathogen, the profile of secreted cytokines from the DCs is also altered to relay information about the nature of the pathogen to naive T cells (Gao et al, 2020;Huang et al, 2001). This pathogen-specific T cell response is critical for the long-term protection against many virulent pathogens (Lo et al, 1999;Bhardwaj et al, 1998;Hess et al, 1996).…”

Immune checkpoint blockade induces gut microbiota translocation that augments extraintestinal anti-tumor immunity

“…MHC class-I-restricted, ovalbuminspecific, CD8+ T cells from OT-I TCR transgenic mice) and measured the activation and functional phenotypes of T cells after the co-culture with DCs (fig. 2D) (26). While OT-I CD8+ T cells primed with DCs pulsed with all bacteria showed significantly higher activation (fig.…”

“…Th1 vs Th17, etc.) (26). In an effort to ascertain whether there was any human clinical data to corroborate our murine findings, we interrogated tumor RNASeq data acquired from 458 human melanoma patients in the Cancer Genome Atlas.…”

“…Translocated bacteria or bacterial components can provide a diverse array of pathogen-associated molecular patterns (PAMPs) capable of agonizing various pattern recognition receptors (PRRs) and thus activating innate immune responses (24,25). Thus, we hypothesized that translocated gut bacterial components activate dendritic cells (DCs) that consequently drive tailored T cell immunity (26).…”