Cytokine release syndrome (CRS) counteracts the effectiveness of chimeric antigen receptor (CAR) T cell therapy in cancer patients, but the mechanism underlying CRS remains unclear. Here, we show that tumor cell pyroptosis triggers CRS during CAR T cell therapy. We find that CAR T cells rapidly activate caspase 3 in target cells through release of granzyme B. The latter cleaves gasdermin E (GSDME), a pore-forming protein highly expressed in B leukemic and other target cells, which results in extensive pyroptosis. Consequently, pyroptosis-released factors activate caspase 1 for GSDMD cleavage in macrophages, which results in the release of cytokines and subsequent CRS. Knocking out GSDME, depleting macrophages, or inhibiting caspase 1 eliminates CRS occurrence in mouse models. In patients, GSDME and lactate dehydrogenase levels are correlated with the severity of CRS. Notably, we find that the quantity of perforin/granzyme B used by CAR T cells rather than existing CD8+ T cells is critical for CAR T cells to induce target cell pyroptosis.

Abstract. Following the recent Global Carbon Project (GCP) synthesis of the decadal methane (CH 4 ) budget over 2000, we analyse here the same dataset with a focus on quasi-decadal and inter-annual variability in CH 4 emissions. The GCP dataset integrates results from topdown studies (exploiting atmospheric observations within an atmospheric inverse-modelling framework) and bottom-up models (including process-based models for estimating land surface emissions and atmospheric chemistry), inventories of anthropogenic emissions, and data-driven approaches.The annual global methane emissions from top-down studies, which by construction match the observed methane growth rate within their uncertainties, all show an increase in total methane emissions over the period [2000][2001][2002][2003][2004][2005][2006][2007][2008][2009][2010][2011][2012], but this increase is not linear over the 13 years. Despite differences between individual studies, the mean emission anomaly of

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Wetlands are thought to be the major contributor to interannual variability in the growth rate of atmospheric methane (CH4) with anomalies driven by the influence of the El Niño-Southern Oscillation (ENSO). Yet it remains unclear whether (i) the increase in total global CH4 emissions during El Niño versus La Niña events is from wetlands and (ii) how large the contribution of wetland CH4 emissions is to the interannual variability of atmospheric CH4. We used a terrestrial ecosystem model that includes permafrost and wetland dynamics to estimate CH4 emissions, forced by three separate meteorological reanalyses and one gridded observational climate dataset, to simulate the spatio-temporal dynamics of wetland CH4 emissions from 1980–2016. The simulations show that while wetland CH4 responds with negative annual anomalies during the El Niño events, the instantaneous growth rate of wetland CH4 emissions exhibits complex phase dynamics. We find that wetland CH4 instantaneous growth rates were declined at the onset of the 2015–2016 El Niño event but then increased to a record-high at later stages of the El Niño event (January through May 2016). We also find evidence for a step increase of CH4 emissions by 7.8±1.6 Tg CH4 yr−1 during 2007–2014 compared to the average of 2000–2006 from simulations using meteorological reanalyses, which is equivalent to a ~3.5 ppb yr−1 rise in CH4 concentrations. The step increase is mainly caused by the expansion of wetland area in the tropics (30°S–30°N) due to an enhancement of tropical precipitation as indicated by the suite of the meteorological reanalyses. Our study highlights the role of wetlands, and the complex temporal phasing with ENSO, in driving the variability and trends of atmospheric CH4 concentrations. In addition, the need to account for uncertainty in meteorological forcings is highlighted in addressing the interannual variability and decadal-scale trends of wetland CH4 fluxes.