No abstract

Protective immune responses to viral infection are initiated by innate immune sensors that survey extracellular and intracellular space for foreign nucleic acids. The existence of these sensors raises fundamental questions about self/nonself discrimination because of the abundance of self-DNA and self-RNA that occupy these same compartments. Recent advances have revealed that enzymes that metabolize or modify endogenous nucleic acids are essential for preventing inappropriate activation of the innate antiviral response. In this review, we discuss rare human diseases caused by dysregulated nucleic acid sensing, focusing primarily on intracellular sensors of nucleic acids. We summarize lessons learned from these disorders, we rationalize the existence of these diseases in the context of evolution, and we propose that this framework may also apply to a number of more common autoimmune diseases for which the underlying genetics and mechanisms are not yet fully understood.

No abstract

SignificanceType I interferons (IFNs) are cytokines that are essential for host defense against virus infection, but when they are inappropriately produced, they can cause severe autoimmune disease in humans. We have found that the sumoylation pathway of protein modification is essential for preventing an ectopic IFN response. Specifically, we have identified SUMO2 and SUMO3 as the two SUMO proteins that redundantly prevent IFN production. Remarkably, the potent IFN response caused by loss of SUMO2/3 is independent of all known inducers of the antiviral response, revealing a distinct mechanism of IFN production that has implications for our understanding of antiviral immunity.

Unremitting defense against diverse pathogens and malignancies requires a dynamic and durable immune response. Tissue-resident memory CD8 + T cells (TRM) afford robust protection against infection and cancer progression through continuous surveillance of non-lymphoid tissues. Here, we provide insight into how TRM confer potent and persistent immunity through partitioning of distinct cellular subsets differing in longevity, effector function, and multipotency. Antigen-specific CD8 + T cells localized to the epithelium of the small intestine are primarily comprised of a shorter-lived effector population most prominent early following both acute viral and bacterial infections, and a longer-lived Id3 hi TRM population that subsequently accumulates at later memory timepoints. We define regulatory gene-programs driving these distinct TRM states, and further clarify roles for Blimp1, T-bet, Id2, and Id3 in supporting and maintaining intestinal TRM heterogeneity during infection. Further, through single-cell RNAseq analysis we demonstrate that tumor-infiltrating lymphocytes broadly differentiate into discrete populations of shortlived and long-lived TRM-like subsets, which share qualities with terminally-exhausted and progenitorexhausted cells, respectively. As the clinical relevance of TRM continues to widen from acute infections to settings of chronic inflammation and malignancy, clarification of the spectrum of phenotypic and functional states exhibited by CD8 + T cells that reside in non-lymphoid tissues will provide a framework for understanding their regulation and identity in diverse pathophysiological contexts.