TY - JOUR
T1 - The inflammasome adaptor ASC intrinsically limits CD4+ T-cell proliferation to help maintain intestinal homeostasis
AU - Khameneh, Hanif Javanmard
AU - Leong, Keith Weng Kit
AU - Mencarelli, Andrea
AU - Vacca, Maurizio
AU - Mambwe, Bezaleel
AU - Neo, Kurt
AU - Tay, Alice
AU - Zolezzi, Francesca
AU - Lee, Bernett
AU - Mortellaro, Alessandra
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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 naive 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.
AB - 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 naive 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.
KW - ASC
KW - CD4+ T cells
KW - Colitis
KW - Inflammasome
KW - Inflammation
UR - http://www.scopus.com/inward/record.url?scp=85069450227&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85069450227&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2019.01566
DO - 10.3389/fimmu.2019.01566
M3 - Article
C2 - 31379813
AN - SCOPUS:85069450227
VL - 10
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
IS - JULY
M1 - 1566
ER -