Eukaryotic cells can initiate several distinct programmes of self-destruction, and the nature of the cell death process (non-inflammatory or proinflammatory) instructs responses of neighbouring cells, which in turn dictates important systemic physiological outcomes. Pyroptosis, or caspase 1-dependent cell death, is inherently inflammatory, is triggered by various pathological stimuli, such as stroke, heart attack or cancer, and is crucial for controlling microbial infections. Pathogens have evolved mechanisms to inhibit pyroptosis, enhancing their ability to persist and cause disease. Ultimately, there is a competition between host and pathogen to regulate pyroptosis, and the outcome dictates life or death of the host.Cells can die through distinct biochemical pathways that produce different morphological and physiological outcomes. Apoptosis is perhaps the most widely recognized programme of cell death, and is mechanistically defined by the requirement for particular cysteinedependent aspartate-specific proteases, or caspases, which produce an orchestrated disassembly of the cell 1 . Apoptotic caspases cleave cellular substrates, resulting in the characteristic features of apoptosis, which include cytoplasmic and nuclear condensation, DNA cleavage and maintenance of an intact plasma membrane. The contents of apoptotic cells are packaged into membrane-enclosed apoptotic bodies, which are targeted for phagocytosis and removal in vivo, resulting in an absence of inflammation 2 (BOX 1).Although apoptosis was the first well-recognized programme of eukaryotic cell death, 'programmed cell death' is broadly applied to several endogenous genetically defined pathways in which the cell plays an active part in its own destruction 3 . Other cell death programmes include autophagy, oncosis and caspase 1-dependent programmed cell death (also known as pyroptosis). Pyroptosis is a more recently identified pathway of host cell death that is stimulated by a range of microbial infections (for example, Salmonella, Francisella and Legionella) and non-infectious stimuli, including host factors produced during myocardial infarction 4 . Caspase 1 was first recognized as a protease that processes the inactive precursors of interleukin 1β (IL-1β) and IL-18 into mature inflammatory cytokines, and was initially called interleukin IL-1β-converting enzyme 5 . However, caspase 1 activation can result not only in the production of activated inflammatory cytokines, but also rapid cell death characterized by plasma-membrane rupture and release of proinflammatory intracellular contents 6,7 . Caspase 1-dependent cell death is a programmed process of cellular self-destruction mediated by caspases, and therefore was not initially distinguished from apoptosis [8][9][10][11] . However, the mechanism, characteristics and outcome of caspase 1-dependent cell death are distinct from apoptosis 6,7,12 . Thus, the term pyroptosis Correspondence to B.T.C. cookson@u.washington.edu. (from the Greek 'pyro', relating to fire or fever, and 'ptosis', meanin...

Caspase-1 cleaves the inactive IL-1␤ and IL-18 precursors into active inflammatory cytokines. In Salmonella-infected macrophages, caspase-1 also mediates a pathway of proinflammatory programmed cell death termed ''pyroptosis.'' We demonstrate active caspase-1 diffusely distributed in the cytoplasm and localized in discrete foci within macrophages responding to either Salmonella infection or intoxication by Bacillus anthracis lethal toxin (LT). Both stimuli triggered caspase-1-dependent lysis in macrophages and dendritic cells. Activation of caspase-1 by LT required binding, uptake, and endosome acidification to mediate translocation of lethal factor (LF) into the host cell cytosol. Catalytically active LF cleaved cytosolic substrates and activated caspase-1 by a mechanism involving proteasome activity and potassium efflux. LT activation of caspase-1 is known to require the inflammasome adapter Nalp1. In contrast, Salmonella infection activated caspase-1 through an independent pathway requiring the inflammasome adapter Ipaf. These distinct mechanisms of caspase-1 activation converged on a common pathway of caspase-1-dependent cell death featuring DNA cleavage, cytokine activation, and, ultimately, cell lysis resulting from the formation of membrane pores between 1.1 and 2.4 nm in diameter and pathological ion fluxes that can be blocked by glycine. These findings demonstrate that distinct activation pathways elicit the conserved cell death effector mechanism of caspase-1-mediated pyroptosis and support the notion that this pathway of proinflammatory programmed cell death is broadly relevant to cell death and inflammation invoked by diverse stimuli.single-cell analysis ͉ apoptosis ͉ inflammasome ͉ inflammation ͉ programmed cell death

We report that oral infection with Yersinia pseudotuberculosis (Yptb) results in development of two distinct populations of pathogen-specific CD8 tissue-resident memory T (TRM) cells in the lamina propria (LP). CD103– T cells did not require transforming-growth factor-β (TGF-β) signaling, but were true resident memory cells. Unlike CD103+ CD8 T cells, which were TGF-β-dependent and scattered in the tissue, CD103– T cells clustered with CD4 T cells and CX3CR1+ macrophages and/or dendritic cells around areas of bacterial infection. CXCR3-dependent recruitment to inflamed areas was critical for development of the CD103– population and pathogen clearance. These studies have identified the preferential development of CD103– LP TRM cells in inflammatory microenvironments within the LP and suggest that this subset plays a critical role in controlling infection.