Biology subjects

Noelle, R. J.

Publications and source records attributed to Noelle, R. J..

3 recordsLinked to original sources

bioRxiv2025

Keratinocyte VISTA attenuates UV light-induced skin injury by suppressing cutaneous type I interferon (IFN-I) response

Persistent production of type I interferons (IFN-Is) is a hallmark of cutaneous lupus erythematosus (CLE). Ultraviolet (UV) light stimulates IFN-I response in the skin and exacerbates CLE. Here, we identify V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) as a negative regulator of both basal and UV-induced IFN-I responses in the skin and show that VISTA limits skin photosensitivity in an IFN-I- dependent manner, in part through Stimulator of Interferon Genes (STING). Furthermore, we demonstrate a novel role for VISTA in keratinocytes both at steady state and in response to UV light. Conditional deletion of VISTA in epidermal keratinocytes results in >10-fold increase in the basal skin IFN-I score and a heightened UV-induced skin injury score, which is dependent on IFN-I signaling. VISTA-targeting monoclonal antibodies suppress UV-induced IFN-I response in human keratinocytes and in mice expressing human VISTA in vivo, which also reduces UV-induced skin injury score. Our findings highlight VISTA as a potential therapeutic target for suppressing IFN-I responses in cutaneous lupus patients who suffer from UV-induced skin inflammation.

immunology↗

bioRxiv2024

Heterogeneity and plasticity of the naive CD4+ T cell compartment

While naive CD4+ T cells have historically been considered a homogenous population, recent studies have provided evidence that functional heterogeneity exists within this population. Using single cell RNA sequencing (scRNAseq), we identify five transcriptionally distinct naive CD4+ T cell subsets that emerge within the single positive stage in the thymus: a quiescence cluster (TQ), a memory-like cluster (TMEM), a TCR reactive cluster (TTCR), an IFN responsive cluster (TIFN), and an undifferentiated cluster (TUND). Elevated expression of transcription factors KLF2, Mx1, and Nur77 within the TQ, TIFN, and TMEM clusters, respectively, allowed enrichment of these subsets for further analyses. Functional studies using sorted cells revealed that naive T cell subsets have distinctive functional biases upon stimulation. Furthermore, treatment of mice with inflammatory stimuli imparted a state of reduced responsiveness on naive T cells, evidenced by a reduction in cytokine production ex vivo. In human lupus patients, naive CD4+ T cell cluster frequencies were distorted, with the TIFN cluster expanding proportionately with disease score. Our data show that naive T cells are influenced by host environment, with functional consequences manifesting upon activation. These findings highlight a need to explore how naive T cells can become distorted in cancer, autoimmunity, and infectious diseases. SummaryThis study describes the transcriptional heterogeneity of murine and human naive CD4+ T cells as comprising of multiple discrete clusters that impact CD4+ T cell fate and trajectories. Naive CD4+ T cells experiencing inflammatory environments exhibit an altered transcriptional state that influences their functional trajectory.

immunology↗

bioRxiv2024

The role of VISTA engagement in limiting neutrophil-mediated inflammation

A growing body of evidence suggests that VISTA, an immune checkpoint inhibitory receptor, plays a central role in the regulation of innate immunity in the settings of inflammatory diseases and cancer. Neutrophils are among the cells that have the highest membrane density of surface VISTA. Targeting VISTA on neutrophils with an agonist antibody resulted in a striking reduction in their LPS-induced peripheral accumulation. Fc receptor engagement was required for anti-VISTA antibody to mediate its effects on neutrophils. Concomitant with reduced peripheral neutrophil cell numbers, anti-VISTA antibody treatment increased neutrophil cell death in the liver. In a murine model of neutrophil-mediated arthritis, agonist anti-VISTA antibody treatment ameliorated disease severity, which was associated with reduced myeloperoxidase activity in the joints. These studies add to a growing spectrum of negative regulatory functions that VISTA performs in controlling inflammation through the innate and adaptive arms of the immune system that has implications for translation into the clinic.

immunology↗