The inflammasome is a critical molecular complex that activates interleukin-1 driven inflammation in response to pathogen-and danger-associated signals. Germline mutations in the inflammasome sensor NLRP1 cause Mendelian systemic autoimmunity and skin cancer susceptibility, but its endogenous regulation remains less understood. Here we use a proteomics screen to uncover dipeptidyl dipeptidase DPP9 as a novel interacting partner with human NLRP1 and a related inflammasome regulator, CARD8. DPP9 functions as an endogenous inhibitor of NLRP1 inflammasome in diverse primary cell types from human and mice. DPP8/9 inhibition via small molecule drugs and CRISPR/Cas9-mediated genetic deletion specifically activate the human NLRP1 inflammasome, leading to ASC speck formation, pyroptotic cell death, and secretion of cleaved interleukin-1␤. Mechanistically, DPP9 interacts with a unique autoproteolytic domain (Function to Find Domain (FIIND)) found in NLRP1 and CARD8. This scaffolding function of DPP9 and its

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Immune sensor proteins are critical to the function of the human innate immune system. The full repertoire of cognate triggers for human immune sensors is not fully understood. Here, we report that human NLRP1 is activated by 3C proteases (3Cpros) of enteroviruses, such as human rhinovirus (HRV). 3Cpros directly cleave human NLRP1 at a single site between Glu130 and Gly131. This cleavage triggers N-glycine–mediated degradation of the autoinhibitory NLRP1 N-terminal fragment via the cullinZER1/ZYG11B complex, which liberates the activating C-terminal fragment. Infection of primary human airway epithelial cells by live human HRV triggers NLRP1-dependent inflammasome activation and IL-18 secretion. Our findings establish 3Cpros as a pathogen-derived trigger for the human NLRP1 inflammasome and suggest that NLRP1 may contribute to inflammatory diseases of the airway.

Human NLRP1 (NACHT, LRR, and PYD domain-containing protein 1) is an innate immune sensor predominantly expressed in the skin and airway epithelium. Here, we report that human NLRP1 senses the ultraviolet B (UVB)- and toxin-induced ribotoxic stress response (RSR). Biochemically, RSR leads to the direct hyperphosphorylation of a human-specific disordered linker region of NLRP1 (NLRP1 DR ) by MAP3K20/ZAKα kinase and its downstream effector, p38. Mutating a single ZAKα phosphorylation site in NLRP1 DR abrogates UVB- and ribotoxin-driven pyroptosis in human keratinocytes. Moreover, fusing NLRP1 DR to CARD8, which is insensitive to RSR by itself, creates a minimal inflammasome sensor for UVB and ribotoxins. These results provide insight into UVB sensing by human skin keratinocytes, identify several ribotoxins as NLRP1 agonists, and establish inflammasome-driven pyroptosis as an integral component of the RSR.

Membrane lipid microdomains (lipid rafts) play an important role in T cell function by forming areas of high lipid order that facilitate activation. However, their role in regulating T cell differentiation and function remains controversial. In this study, by applying a new approach involving microscopy and flow cytometry, we characterize membrane lipid order in ex vivo primary human CD4+ T cells. We reveal that differential membrane lipid order dictates the response to TCR stimulation. T cells with high membrane order formed stable immune synapses and proliferated robustly, intermediate order cells had reduced proliferative ability accompanied by unstable immune synapse formation, whereas low order T cells were profoundly unresponsive to TCR activation. We also observed that T cells from patients with autoimmune rheumatic disease had expanded intermediate order populations compared with healthy volunteers. This may be important in dictating the nature of the immune response since most IFN-γ+CD4+ T cells were confined within intermediate membrane order populations, whereas IL-4+CD4+ T cells were contained within the high order populations. Importantly, we were able to alter T cell function by pharmacologically manipulating membrane order. Thus, the results presented from this study identify that ex vivo CD4+ T cells sustain a gradient of plasma membrane lipid order that influences their function in terms of proliferation and cytokine production. This could represent a new mechanism to control T cell functional plasticity, raising the possibility that therapeutic targeting of membrane lipid order could direct altered immune cell activation in pathology.

Hong et al. show that IFNλ4 exhibits similar antiviral activity to IFNλ3. Humans deploy several mechanisms to limit expression of functional IFNλ4 through noncoding splice variants and nonfunctional protein isoforms.

The cytokine interleukin-22 (IL-22), which is a member of the IL-10 family, is produced exclusively by immune cells and activates signal transducer and activator of transcription 3 (STAT3) in nonimmune cells, such as hepatocytes, keratinocytes, and colonic epithelial cells, to drive various processes central to tissue homeostasis and immunosurveillance. Dysregulation of IL-22 signaling causes inflammatory diseases. IL-22 binding protein (IL-22BP; encoded by IL22RA2) is a soluble IL-22 receptor, which antagonizes IL-22 activity and has genetic associations with autoimmune diseases. Humans have three IL-22BP isoforms, IL-22BPi1 to IL-22BPi3, which are generated by alternative splicing; mice only have an IL-22BPi2 homolog. We showed that, although IL-22BPi3 had less inhibitory activity than IL-22BPi2, IL-22BPi3 was more abundant in various human tissues under homeostatic conditions. IL-22BPi2 was more effective than IL-22BPi3 at blocking the contribution of IL-22 to cooperative gene induction with the inflammatory cytokine IL-17, which is often present with IL-22 in autoimmune settings. In addition, we found that IL-22BPi1 was not secreted and therefore failed to antagonize IL-22 signaling. Furthermore, IL-22BPi2 was the only isoform that was increased in abundance when myeloid cells were activated by Toll-like receptor 2 signaling or retinoic acid, a maturation factor for myeloid cells. These data suggest that the human IL-22BP isoforms have distinct spatial and temporal roles and coordinately fine-tune IL-22-dependent STAT3 responses in tissues as a type of rheostat.

This work demonstrates a stand-alone power source that integrates a paper-based hydrogen fuel cell with a customized chemical heater that produces hydrogen in-situ upon the addition of a liquid. The presented approach operates by capillary action and takes advantage of the hydrogen released as a by-product of an exothermic reaction used in point-of-care diagnostics. The paperbased fuel cell produces a maximum power of 25.8 mW (103.2 mW cm -2 ), which is suitable for powering a diversity of electrical devices such as commercially available digital pregnancy tests and glucometers. While device shape and dimensions can be customized, here it is shown that the fuel cell can be designed in a compact form factor and footprint comparable to a lateral flow test while providing a remarkable power output. This approach holds great promise for powering portable diagnostics, as the generated electric power could enable device functionalities required for advanced assays, such as device timing, actuation, and signal quantification. Part of the same liquid sample that is to be analyzed (urine, saliva, water, etc) could be used to trigger the hydrogen generation and start the fuel cell operation.