IFNγ binding to extracellular matrix prevents fatal systemic toxicity

Interferon-γ (IFNγ) is an important mediator of cellular immune responses, but high systemic levels of this cytokine are associated with immunopathology. IFNγ binds to its receptor (IFNγR) and to extracellular matrix (ECM) via four positively charged C-terminal amino acids (KRKR), the ECM-binding domain (EBD). Across evolution, IFNγ is not well conserved, but the EBD is highly conserved, suggesting a critical function. Here, we show that IFNγ lacking the EBD (IFNγ(ΔKRKR)) does not bind to ECM but still binds to the IFNγR and retains bioactivity. Overexpression of IFNγ(ΔKRKR) in tumors reduced local ECM binding, increased systemic levels and induced sickness behavior, weight loss and toxicity. To analyze the function of the EBD during infection, we generated IFNγ(ΔKRKR) mice lacking the EBD by using CRISPR–Cas9. Infection with lymphocytic choriomeningitis virus resulted in higher systemic IFNγ(ΔKRKR) levels, enhanced sickness behavior, weight loss and fatal toxicity. We conclude that local retention of IFNγ is a pivotal mechanism to protect the organism from systemic toxicity during prolonged immune stimulation

NK1.1⁺ innate lymphoid cells in salivary glands inhibit establishment of tissue-resident memory CD8⁺ T cells in mice

NK1.1+ cells found in salivary glands (SG) represent a unique cell population of innate lymphoid cells (ILC) with characteristics of both conventional NK cells and ILC1. Here, we demonstrate that these NK1.1+ cells limit the accumulation and differentiation of virus‐specific tissue‐resident memory CD8+ T cells (TRM cells) in SG of mice infected with lymphocytic choriomeningitis virus (LCMV). The negative regulation of LCMV‐specific CD8+ TRM cells by NK1.1+ cells in SG is independent of NKG2D, NKp46, TRAIL, and perforin. Moreover, analysis of NKp46iCre+Eomesfl/fl mice revealed that Eomes‐dependent conventional NK cells are dispensable for negative regulation. Since the SG are prone to autoimmune reactions, regulation of TRM cells by tissue‐resident ILC may be particularly important to prevent immunopathology in this organ