Biology subjects

Su, M. A.

Publications and source records attributed to Su, M. A..

8 recordsLinked to original sources

bioRxiv2026

Xist-mediated gene silencing promotes T cell-driven autoimmunity

Four out of five individuals affected by autoimmune disease are female. Yet, sex-specific factors that drive autoimmune predisposition in females remain poorly understood. Recent studies have implicated the female-specific long non-coding RNA Xist in autoimmunity through its ability to activate immune responses as a TLR7 ligand and through the immunogenic properties of Xist-associated proteins, stimulating dendritic cells and B cells. Here, we identify a T cell-intrinsic role for Xist in promoting autoimmunity. T cell-specific Xist deletion in mice had minimal effects on T cell populations at rest but impaired T cell fitness and increased the frequency of regulatory T cells (Tregs) in a competitive transfer setting. Xist deficiency derepressed X-linked genes, including Foxp3, the lineage-defining transcription factor for Tregs and Sh2d1a, encoding the SLAM-associated adaptor SAP, which regulates T cell activation and contraction and is linked to monogenic colitis. Finally, Xist deficiency impaired the colitogenic capacity of CD4+ T cells in an adoptive transfer model. Together, these findings reveal a previously unrecognized role for Xist-mediated gene silencing in supporting CD4+ T cell persistence and colitogenic capacity.

immunology↗

bioRxiv2026

The Histone Methyltransferase KMT2D promotes Natural Killer cell effector molecule release

Natural Killer (NK) cells eliminate virally infected and cancerous cells by secreting cytotoxic granules and pro-inflammatory cytokines. However, the epigenetic mechanisms that coordinate these processes in human NK cells remain poorly understood. We identified two NK deficiency (NKD) patients with mutations in the histone methyltransferase KMT2D that demonstrated impaired cytotoxicity and degranulation. CRISPR-mediated KMT2D deletion or introduction of a patient-specific mutation in healthy human NK cells was sufficient to inhibit effector functions. NK cell-specific KMT2D deletion in mice resulted in defective NK cell degranulation and IFN-{gamma} production, increasing mortality following MCMV infection. KMT2D loss reduced H3K4me1 deposition, associated with decreased levels of RAB3D. RAB3D-deficient human NK cells reduced the release of GZMB and IFN-{gamma}, without impacting intracellular levels. Thus, KMT2D acts as a conserved epigenetic regulator of mature NK cell functions, promoting rapid effector molecule release.

immunology↗

bioRxiv2026

TRPV1-cardiac afferent ablation after completed myocardial infarction prevents arrhythmogenic remodeling

Background Therapies to prevent ventricular arrhythmias after completed myocardial infarction (MI) remain limited. Although TRPV1 afferent ablation at acute MI improves cardiac remodeling, the effect of delayed subacute targeting remains unknown. Objective We investigated whether ablating cardiac TRPV1 afferents during the subacute post-MI window mitigates structural, electrophysiological, and neuro-cardiac axis remodeling to suppress ventricular arrhythmias. Methods Yorkshire pigs underwent sham surgery or anterior MI creation. Two weeks post-MI, animals were randomized to percutaneous epicardial resiniferatoxin (RTX, for cardiac-selective TRPV1 afferent depletion) or vehicle administration. Four weeks later, terminal studies assessed the effects of RTX on cardiac structure and function, ventricular arrhythmogenesis, and neuro-cardiac axis remodeling using in vivo electrophysiologic mapping, real-time neurotransmitter sensing, immunohistochemistry, and transcriptomic profiling. Results Cardiac TRPV1 afferent depletion was confirmed by blunted responses to TRPV1 agonists. RTX-treated animals exhibited improved left ventricular function, reduced end-diastolic diameter, and suppressed ventricular tachycardia/fibrillation (VT/VF) inducibility. Endocardial electroanatomic mapping revealed improved VT/VF electrophysiologic correlates in RTX-treated animals, including fewer deceleration zones and late potentials. Epicardial multielectrode mapping demonstrated reduced electrophysiologic heterogeneity in the scar border zone. Real-time release of adrenergic neurotransmitters (noradrenaline and neuropeptide Y) was normalized during sympathoexcitation in RTX-treated animals. Histologically, RTX treatment attenuated scar border zone myocardial fibrosis and sympathetic nerve sprouting, while suppressing T cell infiltration in cardiac sensory ganglia. Bulk RNA-sequencing of stellate ganglia revealed downregulation of adrenergic genes. Conclusion Cardiac TRPV1 afferent ablation post-completed MI alters disease trajectory by mitigating structural, functional, and neuro-cardiac axis remodeling. Targeting cardiac TRPV1 afferents represents a promising subacute post-MI therapeutic strategy.

physiology↗

bioRxiv2026

Pathologic T cell immunosenescence drives the development of age-associated autoimmune peripheral neuropathy

While certain autoimmune conditions are more common in the young (e.g. Type 1 Diabetes), others are more frequent in the aged. A striking example is chronic inflammatory demyelinating polyneuropathy (CIDP), a CD4+ T cell-mediated autoimmune disease of the peripheral nervous system, which has a peak decade of onset of 70-79 years. How aging predisposes to autoimmunity, however, remains unclear. CD4+ T cells are highly susceptible to age-associated changes, including acquisition of immunosenescent features such as enhanced SA-{beta}-gal activity, increased Cdkn1a (p21) expression, and upregulation of Tnfsf8 (CD153). We show here that CD4+ T cells exhibiting these changes are increased in CIDP patients and mice with CIDP-like disease. These CD4+ T cells exhibit a senescence-associated secretory phenotype (SASP), show functional senescence (i.e., decreased proliferation and resistance to apoptosis), and have enhanced capacity for inciting neuropathy. Notably, a senescent cell-clearing senolytic agent (fisetin) decreased the pathogenic capacity of CD4+ T cells, and a SASP-suppressing senomorphic therapy (ruxolitinib) protected mice against autoimmune demyelination. Together, these findings delineate a key role for age-associated senescent CD4+ T cells in driving age-associated autoimmunity.

immunology↗

bioRxiv2024

Polyfunctional IL-21+ IFNg+ T follicular helper cells contribute to checkpoint inhibitor diabetes mellitus and can be targeted by JAK inhibitor therapy

Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, but their use is limited by the development of autoimmunity in healthy tissues as a side effect of treatment. Such immune-related adverse events (IrAE) contribute to hospitalizations, cancer treatment interruption and even premature death. ICI-induced autoimmune diabetes mellitus (ICI-T1DM) is a life-threatening IrAE that presents with rapid pancreatic beta-islet cell destruction leading to hyperglycemia and life-long insulin dependence. While prior reports have focused on CD8+ T cells, the role for CD4+ T cells in ICI-T1DM is less understood. Here, we identify expansion CD4+ T follicular helper (Tfh) cells expressing interleukin 21 (IL-21) and interferon gamma (IFN{gamma}) as a hallmark of ICI-T1DM. Furthermore, we show that both IL-21 and IFN{gamma} are critical cytokines for autoimmune attack in ICI-T1DM. Because IL-21 and IFN{gamma} both signal through JAK-STAT pathways, we reasoned that JAK inhibitors (JAKi) may protect against ICI-T1DM. Indeed, JAKi provide robust in vivo protection against ICI-T1DM in a mouse model that is associated with decreased islet-infiltrating Tfh cells. Moreover, JAKi therapy impaired Tfh cell differentiation in patients with ICI-T1DM. These studies highlight CD4+ Tfh cells as underrecognized but critical mediators of ICI-T1DM that may be targeted with JAKi to prevent this grave IrAE. VISUAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/625710v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@ed4acdorg.highwire.dtl.DTLVardef@c9e062org.highwire.dtl.DTLVardef@1aa81eforg.highwire.dtl.DTLVardef@1388747_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Clonally-Expanded, Thyrotoxic Autoimmune Mediator CD8+ T cells Driven by IL21 Contribute to Checkpoint Inhibitor Thyroiditis

Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) cancer therapy and is an increasing clinical challenge with the expanding use of these treatments. To date, human immunopathogenic studies of immune related adverse events (IRAEs) have relied upon sampling of circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from subjects with ICI-thyroiditis, one of the most common IRAEs, and compared immune infiltrates to those from subjects with spontaneous autoimmune Hashimotos thyroiditis (HT) or no thyroid disease. Single cell RNA sequencing revealed a dominant, clonally expanded population of thyroid-infiltrating cytotoxic CXCR6+ CD8+ T cells ("CD8+ autoimmune mediators) present in ICI-thyroiditis, but not HT or healthy controls. Furthermore, we identified a crucial role for interleukin 21, a cytokine secreted by intrathyroidal T follicular (Tfh) and T peripheral helper (Tph) cells, as a driver of these thyrotoxic CD8+ autoimmune mediators. In the presence of IL21, human CD8+ T cells acquired the autoimmune mediator phenotype with upregulation of cytotoxic molecules (IFN{gamma}, granzyme); the chemokine receptor CXCR6; and thyrotoxic capacity. We validated these findings in vivo using a novel mouse model of IRAEs, and further demonstrated that genetic blockade of IL21 signaling protected ICI-treated mice from thyroid immune infiltration. Taken together these studies reveal novel mechanisms and therapeutic targets by which IL21+ Tfh/Tph cells drive thyrotoxic CD8+ autoimmune mediators for the development of IRAEs in humans. One Sentence SummaryScRNAseq reveals a novel role for CD8+ autoimmune mediators and IL21+ T helper cells in the pathogenesis of human checkpoint inhibitor thyroiditis.

immunology↗

bioRxiv2022

Sex differences in NK cells mediated by the X-linked epigenetic regulator UTX

Viral infection outcomes are sex-biased, with males generally more susceptible than females. Paradoxically, the numbers of anti-viral natural killer (NK) cells are increased in males compared to females. Using samples from mice and humans, we demonstrate that while numbers of male NK cells are increased compared to females, they display impaired production of the anti-viral cytokine IFN-{gamma}. These sex differences were not due solely to divergent levels of gonadal hormones, since these differences persisted in gonadectomized mice. Instead, these differences can be attributed to lower male expression of X-linked Kdm6a (UTX), an epigenetic regulator which escapes X inactivation in female NK cells. NK cell-specific UTX deletion in females phenocopied multiple features of male NK cells, which include increased numbers and reduced IFN-{gamma} production. Integrative ATAC-seq and RNA-seq analysis revealed a critical role for UTX in the regulation of chromatin accessibility and gene expression at loci important in NK cell homeostasis and effector function. Consequently, NK cell-intrinsic UTX levels are critical for optimal anti-viral immunity, since mice with NK cell-intrinsic UTX deficiency show increased lethality to mouse cytomegalovirus (MCMV) challenge. Taken together, these data implicate UTX as a critical molecular determinant of NK cell sex differences and suggest enhancing UTX function as a new strategy to boost endogenous NK cell anti-viral responses.

immunology↗

bioRxiv2022

Inhibition of the IL-17A axis Protects against Immune-related Adverse Events while Supporting Checkpoint Inhibitor Anti-tumor Efficacy

Checkpoint inhibitor (ICI) immunotherapy leverages the bodys own immune system to attack cancer cells but leads to unwanted autoimmune side effects in up to 60% of patients. Such immune related adverse events (IrAE) may lead to treatment interruption, permanent organ dysfunction, hospitalization and premature death. Thyroiditis is one of the most common IrAE, but the cause of thyroid IrAE remains unknown. Here we present a novel mouse model in which checkpoint inhibitor therapy leads to multi-organ autoimmune infiltrates and show that activation and infiltration of Type 3 immune cells including IL17A+ ROR{gamma}t+ CD4+ (T helper 17 or Th17) and gamma delta 17 ({gamma}{delta}T17) T cells promote thyroid IrAE development. IL-17A+ T cells were similarly found in thyroid specimens from cancer patients treated with ICI who developed thyroid IrAE. Furthermore, antibody-based inhibition of IL-17A, a clinically available therapy, significantly reduced thyroid IrAE development in ICI-treated mice. Finally, combination of IL-17A neutralization with ICI treatment in multiple tumor models did not reduce ICI anti-tumor efficacy. These studies suggest that targeting Th17 and {gamma}{delta}17 function may reduce IrAE without impairing ICI anti-tumor efficacy and may be a generalizable strategy to address IL17-mediated IrAE.

immunology↗