S. G. M. received honoraria for lecturing and travel expenses for attending meetings and has received financial research support from Bayer, Biogen

Idec, Sanofi-Aventis, Bayer Schering, Merck Serono, Novo Nordisk, Genzyme, MSD and Teva. All authors declare no relevant conflicts of interest. “
“Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an important component of the inflammasome, INK 128 mouse functioning as an adaptor protein that facilitates the recruitment and activation of procaspases that in turn promote the maturation of interleukin-1β (IL-1β) and IL-18. Despite initial focus on the inflammatory properties of ASC there is emerging evidence that highlights the Fulvestrant concentration importance of ASC in facilitating adaptive immune

responses. However, the cellular and molecular basis for the involvement of ASC in adaptive immunity remains largely unexplored. We have previously demonstrated that activated ASC-deficient T cells have dampened proliferative responses. We have therefore explored the underlying cellular mechanism(s) by which ASC regulates T-cell proliferation. We show that under activating conditions (anti-CD3/CD28 stimulation) in bulk T-cell cultures the presence of ASC−/− CD4+ T cells is sufficient to suppress the proliferative responses of neighbouring T cells. Furthermore, ASC−/− CD4+ T cells upon activation exhibit a suppressive cytokine profile, with elevated production of IL-10 and reduced secretion of T helper type 1 cytokines, interferon-γ and IL-2. This increase in IL-10 secretion within the activated ASC−/− CD4+ T-cell compartment Phospholipase D1 was not associated with a proportional increase in conventional Foxp3+ regulatory T (Treg) cells. Interestingly, when equal numbers of fluorescence-activated cell sorted ASC+/+ and ASC−/− Treg cells (CD4+ CD44intermediate/high CD25+) were activated in vitro, the ASC−/− fraction produced significantly more IL-10 than their wild-type counterparts, suggesting that ASC−/− Treg cells have greater suppressive capacity. Collectively,

these results imply that the ASC may influence the development and functioning of Treg cells. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an integral component of the inflammasome, a cytosolic multiprotein platform that facilitates the activation of pro-inflammatory caspases, which in turn promote the maturation and subsequent secretion of interleukin-1β (IL-1β) and IL-18.1,2 ASC is a simple adaptor protein with two linked protein–protein interaction domains of the death domain superfamily: an N-terminal pyrin/PAAD death domain and a C-terminal caspase recruitment domain, which interact with the different NOD-like receptors, the sensory elements of the inflammasome and pro-caspase-1, respectively.3–5 These two domains enable ASC to function as an essential link between the sensor protein and effector molecules during inflammasome assembly.