The immune system integrates signals to regulate immune responses, forming complex context-dependent networks where identical cues produce distinct outcomes. Signal transducer and activator of transcription (STAT) transcription factors convert cytokine receptor engagement into transcriptional responses, serving as central regulatory hubs. How concurrent STAT activation across different environments shapes immune cell function remains unclear. Here, we show that STAT3 plays a context-dependent role in antiviral natural killer (NK) cells, either promoting or impairing adaptive responses depending on the inflammatory milieu during mouse cytomegalovirus (MCMV) infection. STAT3 is recruited to distinct genomic loci depending on IL-15 or type I interferon availability, thus driving alternative transcriptional programs. Mechanistically, STAT3 differentially regulates downstream transcription factors MYB and B lymphocyte–induced maturation protein-1 (BLIMP-1) to shape NK cell differentiation during homeostasis and infection. STAT3 relocation is governed by epigenetic mechanisms and preferred relocation toward distinct STAT motifs. Thus, STAT3 functions as a cytokine-sensing transcriptional switch integrating IL-15 and type I interferon signals to control lymphocyte adaptation during viral infection.
Glycans play fundamental roles in T cell biology; however, the glycome landscape of γδ T cells remains to be unlocked. Despite the growing importance of γδ T cells in host defense, tissue homeostasis, and diseases, the glycosylation mechanisms guiding their activation, commitment, and function remain poorly defined. By performing single-cell RNA sequencing, we revealed that type 3/γδ T17/interleukin-17A (IL-17A)–committed γδ T cells rely on ( N-acetylglucosaminyltransferase 1 ) MGAT1 – MGAT5 –mediated branched N-glycosylation. We further demonstrated that the absence of branched N -glycans on γδ T cells acts as a peripheral signal, driving an IL-17A–pro-inflammatory phenotype, alongside a shift to a Vγ4 + subset and the imprinting of innate-like properties. This altered glycoform of type 3 γδ T cells was shown to induce severe psoriasis. γδ T cells from patients with autoimmune and inflammatory diseases exhibited a deficiency in branched N -glycans. Glycan supplementation can reprogram γδ T cells toward a less-pathogenic state, highlighting N -glycans as a previously unrecognized immune checkpoint for γδ T cells.
Innate-like B cells produce natural antibodies and include marginal zone (MZ) B cells and B1 cells. B1 cells are well characterized in mice, where they prenatally seed serous cavities and produce regulatory cytokines. Putative B1 cells have been identified in human prenatal organs, but whether they persist into adulthood remains unclear. Here, we identified B1-like cells in the IgM + and IgA + memory compartment across adult human organs. These cells transcriptionally resembled murine and human prenatal B1 cells but not MZ B cells. They expressed canonical murine B1 cell markers, including AHNAK , and spontaneously secreted IgM. B cell receptor sequencing of paired kidney-spleen samples revealed lower diversity and mutation rates in kidney IgM/IgA clones, suggesting spleen-independent seeding. Adult B1-like cells expressed the regulatory cytokine TGFB and had abundant inferred interactions with tissue myeloid cells, which reciprocally expressed B cell prosurvival cytokines. These findings support the presence of B1-like cells across adult human organs in homeostasis.
Stimulator of interferon genes (STING) is a highly conserved signaling molecule that coordinates an antiviral innate immune response through activation of the nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF3) signaling pathways. In addition to an antiviral response, STING-mediated NF-κB signaling also leads to an inflammatory response, which can cause substantial pathology. However, the molecular mechanism whereby STING drives inflammation is poorly understood, and this has hindered the development of anti-inflammatory strategies targeting this pathway. Here, we define an evolutionarily conserved mechanism whereby STING activates NF-κB signaling via recruitment of inhibitor of NF-κB kinase subunit γ (IKKγ) in an M1-linked ubiquitin-dependent manner. We also show that the more recently evolved carboxyl-terminal tail of STING cooperates with the IKKγ-IKK complex for NF-κB–dependent expression of pro-inflammatory genes in mammalian cells through the kinases TBK1 (TANK-binding kinase 1)/IKKε. Thus, the expression of the key inflammatory genes CCL3 and CCL4 requires the formation of M1-linked ubiquitin and the activation of NF-κB, but we do not detect a role for IRF3 in STING-driven NF-κB signaling.
Peyer’s patches (PPs) in the intestinal mucosa coordinate antibody responses to luminal microbes and dietary antigens. The follicle-associated epithelium (FAE) is traditionally recognized by the presence of microfold cells (M cells) that mediate antigen sampling in PPs. By analyzing Gfi1b -eGFP reporter mice and human PP biopsies, we identified tuft cells as an additional, evolutionarily conserved FAE population that regulates mucosal immunity. Using mouse models and intestinal organoids, we demonstrate that M cells and tuft cells are distinct lineages arising from Pou2f3 + progenitors, whose differentiation is reciprocally regulated by RANKL and interleukin-13 (IL-13), respectively. Tuft cell–derived IL-25 activates type 2 innate lymphoid cells (ILC2s) in PPs. Furthermore, IL-13 production by ILC2 enhances immunoglobulin A class switching and antigen-specific immunity. These findings reveal a dual surveillance system in the FAE, where developmentally related epithelial lineages use distinct mechanisms to coordinate mucosal immunity.
