Many helminth parasites migrate through multiple host organs during infection, but how immune responses are relayed across these tissues is still poorly understood. To investigate the immune aspects of intertissue communication during infection, we established a percutaneous infection model with the tissue-migrating nematode Nippostrongylus brasiliensis. Profiling of the initial cutaneous immune response revealed that dermal gamma delta T cells become activated via an interleukin 1 receptor (IL-1R)-dependent mechanism, engage cell motility-associated transcriptional pathways, and leave the skin after parasite invasion. Inhibition of leukocyte migration prevents the accumulation of IL-17-producing gamma delta T cells in the lungs. Bypassing the skin phase of infection, and thereby preventing dermal gamma delta T cell migration, dampens early IL-17 production in the lungs. This, instead, leads to an enhanced interferon-gamma (IFN-gamma) response together with increased lung damage. Collectively, our data highlight a critical skin-lung axis regulating host-parasite interactions and safeguarding lung health.
Malignant ascites is caused by the peritoneal dissemination of cancer and has a poor prognosis. Here, we performed multiomic analyses on ascites samples from patients with cancer and identified RORC-expressing dendritic cells (RORC DCs) enriched in malignant ascites. RORC DCs expressed PIGR and were transcriptionally similar to murine ROR gamma t+ DCs/Thetis cells implicated in immune tolerance. We devised a high-purity sorting strategy to enable in vitro experiments with patient-derived RORC DCs, which indicated that these cells were phenotypically stable and stimulated T cell proliferation while attenuating IFNG expression. Multiplexed immunofluorescence identified RORC DCs in primary tumors and demonstrated their enrichment in regional lymph node metastases. These results associate human RORC DCs with advanced malignancies and suggest a role for these cells in the tumor microenvironment.
In vivo cell engineering enables the direct programming of immune cells inside patients. Instead of isolating, modifying, and reinfusing cells, therapeutic instructions are delivered directly to selected immune cells through lipid nanoparticles or viral vectors. This approach could facilitate rapid and scalable deployment of varied immune cell therapies across disease contexts. Early clinical studies in oncology and autoimmunity demonstrate increasing technical and clinical feasibility. The next challenge lies in enhancing precision to ensure that vectors reach the target cell type and tissue, deliver the appropriate payload, and produce desired transient or durable activity. Progress in targeting ligands, vector design, biodistribution control, and genome editing is beginning to address these barriers. Ensuring safety against immunogenicity, inflammatory toxicity, off-target editing, and uncontrolled persistence remains a central priority. By mastering these constraints, in vivo engineering could turn endogenous immune cells into therapeutic agents generated directly in the body, expanding cell therapy to diseases refractory to current modalities.
The interleukin-36 receptor (IL-36R) drives proinflammatory signaling and is therapeutically targeted by spesolimab in acute skin inflammation. Beyond its three canonical agonists (IL-36α, IL-36β, and IL-36γ), IL-36R was recently proposed to be activated by IL-37. Together with antagonism by IL-36R antagonist (IL-36RA) and IL-38, this creates a complex structure-function landscape that remains poorly understood. Here, we report the cryo–electron microscopy (cryo-EM) structure of human IL-36γ bound to IL-36R and the shared co-receptor IL-1R accessory protein (IL-1RAcP). IL-36γ engages IL-36R with low affinity, enabling high-affinity IL-1RAcP recruitment. IL-37 exhibits the opposite binding signature, binding IL-36R with high affinity but IL-1RAcP weakly. Functional comparison of IL-36R engagement by IL-36γ and IL-37 confirmed their common proinflammatory signature, with IL-36γ exhibiting markedly higher potency, consistent with its more stable signaling complex. Structural comparison of cytokine-bound versus antibody-antagonized IL-36R revealed that spesolimab acts as an allosteric antagonist. This study therefore provides a structural and mechanistic blueprint for IL-36R activation by distinct cytokines.
