Jakob N. Arnold

Age-related macular degeneration (AMD) represents one of the therapeutic challenges of aging eye diseases. Our investigation reveals the stimulator of interferon genes (STING) pathway as an orchestrator of immune-mediated retinal degeneration, exhibiting biphasic, stage-dependent functionality—providing cytoprotection in healthy tissue but driving pathogenic inflammation during early AMD progression. Through immunohistochemical analysis of human eyes, we demonstrate stage-dependent cytoplasmic STING upregulation with parallel IFN-β activation. Using patient-derived induced pluripotent stem cells-retinal pigment epithelium (iPSC-RPE) from AMD siblings, we discovered polarized cytokine secretion: apical IFN-β triggers photoreceptor apoptosis in human retinal organoids, while basal IL-17A compromises choroidal neovascularization. The Cryba1 conditional knockout (cKO) AMD-like mouse model confirms STING-driven IL-17A expression, while Il17a knock-in mice substantiate vascular alterations. STING activation establishes a pathogenic feed-forward loop between interferons and IL-17A. Single-cell transcriptomics following AAV2-mediated IFN-β overexpression reveals metabolic and phototransduction dysregulation. Both pharmacological STING inhibition with SN-011 and genetic approaches demonstrate therapeutic rescue. Cryba1 / Sting double heterozygous (dhet) mice maintain homeostatic gene expression preserving retinal architecture and function. These findings establish STING as the master regulator simultaneously controlling multiple AMD pathologies through spatially organized inflammation, transforming from protective surveillance to pathogenic driver, and identifying a unified therapeutic target with demonstrated functional rescue across multiple experimental paradigms.

γδ T cells maintain intestinal immune homeostasis, but their contributions to human ulcerative colitis (UC) are poorly understood. We characterized γδ T cells in intestinal biopsies obtained from patients with UC and healthy donors using single-cell RNA sequencing, T cell receptor profiling, and mass cytometry. UC reduced CD103 ⁺ Vγ4Vδ1 ⁺ γδ intraepithelial lymphocytes (γδ IELs) and increased γδ T cell subsets with stemlike phenotypes expressing TCF-1 (T cell factor 1) and PD-1 (programmed cell death receptor 1) or effector-like phenotypes expressing granzyme B, perforin, and T-bet in the lamina propria. γδ T cell composition changes in UC correlated with decreased expression of epithelial BTNL3 and BTNL8 and increased BTN3A1 and BTN3A3 , suggesting altered recruitment and activation. Clinical improvement recovered γδ IELs and reduced inflammation-associated subsets. Inflammation-associated changes were observed in peripheral blood γδ T cells. Thus, distinct γδ T cell subsets in different niches exert protective or pathogenic functions in UC.