Abstract
The inflammasome is a multi-protein complex that mediates proteolytic cleavage and release of the pro-inflammatory cytokines IL-1β and IL-18, and pyroptosis—a form of cell death induced by various pathogenic bacteria. Apoptosis-associated speck-like protein containing a CARD (ASC) has a pivotal role in inflammasome assembly and activation. While ASC function has been primarily implicated in innate immune cells, its contribution to lymphocyte biology is unclear. Here we report that ASC is constitutively expressed in naïve CD4+ T cells together with the inflammasome sensor NLRP3 and caspase-1. When adoptively transferred in immunocompromised Rag1−/− mice, Asc−/− CD4+ T cells exacerbate T-cell-mediated autoimmune colitis. Asc−/− CD4+ T cells exhibit a higher proliferative capacity in vitro than wild-type CD4+ T cells. The increased expansion of Asc−/− CD4+ T cells in vivo correlated with robust TCR-mediated activation, inflammatory activity, and higher metabolic profile toward a highly glycolytic phenotype. These findings identify ASC as a crucial intrinsic regulator of CD4+ T-cell expansion that serves to maintain intestinal homeostasis.
Highlights
Apoptosis-associated speck-like protein containing a CARD (ASC) was originally identified as a protein encoded by the Pycard gene [1,2,3]
We detected a higher proportion of splenic CD4+ T cells expressing the chemokine receptors CCR2 and CCR9 in Asc−/− mice compared to WT mice (Figure 1A)
To examine whether the inflammasome sensor NLRP3 may be involved in this process, we evaluated the course of colitis in Rag1−/− mice receiving naïve CD4+ T cells sorted from the spleen of Nlrp3−/− mice
Summary
Apoptosis-associated speck-like protein containing a CARD (ASC) was originally identified as a protein encoded by the Pycard gene [1,2,3]. ASC has been widely studied in innate immune cells (macrophages, dendritic cells, and neutrophils) as an adaptor molecule of the multiprotein signaling complex known as the inflammasome. ASC is central to the formation of different inflammasome complexes comprising the NLRP1 [5], NLRP3 [6, 7], NLRP6 [8, 9], AIM2 [10], and NLRC4 [11,12,13] sensor molecules. These sensor molecules undergo conformational changes that catalyze ASC oligomerization to form a macromolecular signaling platform known as the ASC “speck.” ASC recruits the cysteine protease caspase-1 via its C-terminal CARD domain [14,15,16].
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