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Neutrophils can efficiently trigger cytotoxicity toward tumor cells and other target cells upon engagement of the IgA receptor CD89. However, the cell-intrinsic factors that influence the induction of cell death upon exposure to neutrophil effector mechanisms in vivo remain largely unknown. To uncover genetic regulators that influence target cell sensitivity to IgA-induced neutrophil-mediated killing, we used a human CD89 (hCD89) transgenic mouse model in which IgA-mediated killing of Her2-positive CD47-deficient murine target cells is mediated by neutrophils. Using a genome-wide in vivo screening approach, we demonstrate that deletion of the gene encoding inositol-tetrakisphosphate 1 kinase (ITPK1) increases survival of target cells in anti-Her2 IgA-treated mice. Moreover, we show that this effect depends on neutrophil activity and on the ITPK1 kinase domain. Notably, ITPK1 deficiency did not measurably impact survival of IgA-opsonized target cells in in vitro systems, underscoring the importance of in vivo screening systems to uncover physiologically relevant regulators of neutrophil killing.

EBV-induced gene 3 (Ebi3) is a β subunit within the IL-12 cytokine family that canonically binds to α subunits p19, p28, or p35 to form the heterodimeric cytokines IL-39, IL-27, and IL-35, respectively. In the last decade, the binding partners for Ebi3 have continued to expand to include IL-6 and the other IL-12 family β subunit p40, revealing the possibility that Ebi3 may be able to bind to other cytokines and have distinct functions. We first explored this possibility utilizing an in vivo mouse model of regulatory T cell–restricted deletions of the subunits composing the cytokine IL-35, p35, and Ebi3, and we observed a differential impact on CD8⁺ T cell inhibitory receptor expression despite comparable reduction in tumor growth. We then screened the ability of Ebi3 to bind to different cytokines with varying structural resemblance to the IL-12 family α subunits. These in vitro screens revealed extracellular binding of Ebi3 to both IFN-γ and IL-10. Ebi3 bound to IFN-γ and IL-10 abrogated signal transduction and downstream functions of both cytokines. Lastly, we validated that extracellular complex formation after mixing native proteins resulted in loss of function. These data suggest that secreted partnerless Ebi3 may bind to cytokines within the extracellular microenvironment and act as a cytokine sink, further expanding the potential immunological impact of Ebi3.

In aquatic ectotherms, temperature plays a pivotal role in biological processes and the prevalence of viral diseases; however, the molecular mechanisms underlying these effects are not fully elucidated. In this study, we investigate the impact of elevated temperatures (32°C) on the immune response against white spot syndrome virus (WSSV) in shrimp (Litopenaeus vannamei). Our findings reveal that higher water temperatures, specifically 32°C, significantly inhibit WSSV replication and pathogenicity, thereby enhancing the survival rates of infected shrimp. Through transcriptome analysis and in vivo experiments, we identified heat shock protein 70 (HSP70) as a key factor in this thermal regulation of immunity. Shrimp maintained at 32°C, with silenced HSP70 expression, exhibited increased viral loads and reduced survival, underscoring the crucial protective role of HSP70 against WSSV at elevated temperatures. Our results further uncover the HSP70–Toll4–Dorsal–antimicrobial peptide (AMP) pathway as a key mediator of WSSV resistance at elevated temperatures. This pathway involves the interaction of HSP70 with the Toll4 receptor, resulting in the phosphorylation of Dorsal and the consequent modulation of expression of AMPs such as the anti–LPS factor (ALF) and lysozyme (LYZ) families. Taken together, these findings advance our understanding of temperature’s role in disease dynamics in aquatic ectotherms, especially the unexpected roles of HSP70 in shrimp in facilitating the innate immune system’s response to thermal stress, and suggest new approaches to managing WSSV in shrimp farming, such as environmental temperature control or HSP70 induction.