Biology subjects

Taylor, K. E.

Publications and source records attributed to Taylor, K. E..

6 recordsLinked to original sources

bioRxiv2026

Folate metabolism in tumor-associated macrophages drives immunosuppressive function to promote tumor growth

Tumor-associated macrophages (TAMs) promote tumor growth, inhibit effector lymphocytes, and induce resistance to immune checkpoint inhibitors (ICI). Therapies designed to deplete TAMs have had little success in the clinic, and strategies aimed to repolarize immunosuppressive TAMs to pro-inflammatory states have struggled with systemic toxicity. We have identified that the combination of low folate in the tumor microenvironment and TAM dependency on the high affinity folate receptor beta (FR{beta}) for folate uptake results in a unique metabolic dependency of TAMs necessary for their immunosuppressive function. FR{beta} (encoded by Folr2) is uniquely expressed on myeloid cells and upregulated on TAMs. FR{beta}+ TAMs exhibit an immunosuppressive phenotype in melanoma and are associated with worse clinical outcomes and resistance to ICI in melanoma patients. We generated a novel Folr2-/- mouse model to study why TAMs express a unique folate receptor and showed that tumor growth was slowed in the absence of Folr2 in a T-cell dependent manner. We observed a dramatic repolarization of Folr2-/- TAMs in vivo to pro-inflammatory states, resulting in increased cytotoxic T cell and NK cell infiltration into tumors. Importantly, we show that folate is low in the tumor microenvironment by performing metabolomics on melanoma tumors and adjacent normal tissue from warm autopsy patient specimens, and that we could increase tumor growth in Folr2-/- mice by increasing serum folate to supraphysiologic concentrations with a high folate diet. Integrated metabolomics and transcriptomic analysis demonstrated that Folr2-/- macrophages have impaired folate uptake and 1C metabolism-based reduction of oxidized glutathione in low folate conditions, resulting in increased mitochondrial reactive oxygen species (ROS) in Folr2-/- cells. Excess ROS results in leakage of mitochondrial DNA into the cytoplasm, activating cGAS-STING signaling and promoting pro-inflammatory macrophage polarization through TBK1 and NF-kB. Together, our data demonstrate that TAM expression of FR{beta} promotes their immunosuppressive functions by maintaining folate uptake in the low folate tumor microenvironment, suggesting that FR{beta} is a novel metabolic checkpoint on TAMs.

immunology↗

bioRxiv2026

Rhodopsin is a tunable capacitor buffering the toxic, desensitizing retinoids of the vertebrate eye

The eye is a marvel of evolution, but visual sensitivity introduces the risk of blinding photodamage. Here we reveal that the locus of sensitivity--the visual pigment rhodopsin --moonlights as a tunable mechanism of retinal photoprotection. Independent of signaling, light activated rhodopsin (R*) serves as an overflow capacitor buffering all-trans retinal (atRAL), a toxic and desensitizing retinoid agonist that accumulates as lipofuscin--a clinical marker of macular degeneration. Across mammals, R* stability reflects binding affinity and sequestration of atRAL (capacitance), thereby mitigating phototoxicity to a degree proportional to species photodamage risk, with human R* uniquely non-protective. A mouse model of defective atRAL clearance treated with a synthetic R* of unnaturally high atRAL capacitance preserved retinal function following light damage. This gene therapy also provided supra-physiological scotopic sensitivity despite being a signal-silent receptor, shielding neighboring dark-state receptors from agonist interference during regeneration, while also enhancing the signaling of endogenous R*. While the consensus human rhodopsin is not photoprotective, during recent evolution, mutations that protect against light damage emerged in high irradiance human environments and are now significantly associated with a 38% reduced risk of blindness and low vision. Together, our findings redefine rhodopsin as a tunable light buffer that can be leveraged to enhance photoreceptor function beyond natural limits.

biochemistry↗

bioRxiv2025

Single-cell RNA sequencing of peripheral blood defines two immunological subtypes of Sjögren's disease

Sjogrens disease (SjD) is a heterogeneous autoimmune disorder with significant clinical and molecular diversity. While anti-SSA antibodies serve as a hallmark serological biomarker, nearly half of patients lack them, raising fundamental questions about distinct pathogenic mechanisms. To address this, we performed single-cell RNA sequencing with surface protein profiling on 1.5 million PBMCs from 333 participants in the Sjogrens International Collaborative Clinical Alliance cohort, comparing those with and without SjD and stratifying them by anti-SSA status. Our analysis identified two immunologically distinct subtypes of SjD, with SSA-positive patients exhibiting a dominant and persistent IFN-I signature, profoundly impacting immune cell maturation. Notably, transitional B cells were disproportionately affected, displaying signs of premature maturation, reduced BCR diversity, and shorter CDR3 regions, reinforced interactions with proinflammatory cells, thereby fostering an environment conducive to autoreactivity. By contrast, SSA-negative SjD participants lacked an upregulated IFN-I signature, challenging prevailing pathogenic models and suggesting alternative immune dysregulation pathways. These findings support a two-disease model of SjD and highlight transitional B cells as both a key biomarker and a potential therapeutic target. Targeting IFN-I signaling and transitional B cell maturation may represent a novel therapeutic avenue to modulate immune dysregulation and prevent autoreactivity in SjD.

genomics↗

bioRxiv2023

Cell-Specific Transposable Element Gene Expression Analysis Identifies Associations with Systemic Lupus Erythematosus Phenotypes

There is an established yet unexplained link between interferon (IFN) and systemic lupus erythematosus (SLE). The expression of sequences derived from transposable elements (TEs) may contribute to production of type I IFNs and generation of autoantibodies. We profiled cell-sorted RNA-seq data (CD4+ T cells, CD14+ monocytes, CD19+ B cells, and NK cells) from PBMCs of 120 SLE patients and quantified TE expression identifying 27,135 TEs. We tested for differential TE expression across 10 SLE phenotypes including autoantibody production and disease activity and discovered 731 differentially expressed (DE) TEs whose effects were mostly cell-specific and phenotype-specific. DE TEs were enriched for specific families and viral genes encoded in TE sequences. Increased expression of DE TEs was associated with genes involved in antiviral activity such as LY6E, ISG15, TRIM22 and pathways such as interferon signaling. These findings suggest that expression of TEs contributes to activation of SLE-related mechanisms in a cell-specific manner, which can impact disease diagnostics and therapeutics.

molecular biology↗

bioRxiv2020

Ethnicity-specific transcriptomic variation in immune cells and correlation with disease activity in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease in which outcomes vary among different racial groups. The aim of this study is to leverage large-scale transcriptomic data from diverse populations to better sub-classify SLE patients into more clinically actionable groups. We leverage cell sorted RNA-seq data (CD14+ monocytes, B cells, CD4+T cells, and NK cells) from 120 SLE patients (63 Asian and 57 White individuals) and apply a four tier analytical approach to identify SLE subgroups within this multiethnic cohort: unsupervised clustering, differential expression analyses, gene co-expression analyses, and machine learning. K-means clustering on the individual cell type data resulted in three clusters for CD4 and CD14, and two clusters for B cells and NK cells. Correlation analysis revealed significant positive associations between the transcriptomic clusters of each immune cell and clinical parameters including disease activity and ethnicity. We then explored differentially expressed genes between Asian and White groups for each cell-type. The shared differentially expressed genes across the four cell types were involved in SLE or other autoimmune related pathways. Co-expression analysis identified similarly regulated genes across samples and grouped these genes into modules. Samples were grouped into White-high, Asians-high (high disease activity defined by SLEDAI score >=6) and White-low, Asians-low (SLEDAI < 6). Random forest classification of disease activity in the White and Asian cohorts showed the best classification in CD4+ T cells in White. The results from these analyses will help stratify patients based on their gene expression signatures to enable precision medicine for SLE.

bioinformatics↗

bioRxiv2019

Complement component 4 genes contribute sex-specific vulnerability in diverse illnesses

Many common illnesses differentially affect men and women for unknown reasons. The autoimmune diseases lupus and Sjogrens syndrome affect nine times more women than men1,2, whereas schizophrenia affects men more frequently and severely3-5. All three illnesses have their strongest common-genetic associations in the Major Histocompatibility Complex (MHC) locus, an association that in lupus and Sjogrens syndrome has long been thought to arise from HLA alleles6-13. Here we show that the complement component 4 (C4) genes in the MHC locus, recently found to increase risk for schizophrenia14, generate 7-fold variation in risk for lupus (95% CI: 5.88-8.61; p < 10-117 in total) and 16-fold variation in risk for Sjogrens syndrome (95% CI: 8.59-30.89; p < 10-23 in total), with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia, greatly reduced risk for lupus and Sjogrens syndrome. In all three illnesses, C4 alleles acted more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for lupus and 31-fold variation in risk for Sjogrens syndrome in men (vs. 6-fold and 15-fold among women respectively) and affected schizophrenia risk about twice as strongly in men as in women. At a protein level, both C4 and its effector (C3) were present at greater levels in men than women in cerebrospinal fluid (p < 10-5 for both C4 and C3) and plasma among adults ages 20-5015-17, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help explain the larger effects of C4 alleles in men, womens greater risk of SLE and Sjogrens, and mens greater vulnerability in schizophrenia. These results nominate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

genetics↗