Biology subjects

Lechner, M. G.

Publications and source records attributed to Lechner, M. G..

7 recordsLinked to original sources

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

UTX Epigenetically Imposes a Cytolytic Effector Program in Autoreactive Stem-like CD8+ T cell Progenitors

Type 1 Diabetes Mellitus (T1D) is a chronic disease caused by an unremitting autoimmune attack on pancreatic beta cells. This autoimmune chronicity is mediated by stem-like progenitor CD8+ T cells that continually repopulate the pool of beta cell-specific cytolytic effectors. Factors governing the conversion of progenitors to effectors, however, remain unclear. T1D has been linked to a chromosomal region (Xp13-p11) that contains the epigenetic regulator UTX, which suggests a key role for UTX in T1D pathogenesis. Here, we show that T cell-specific UTX deletion in NOD mice protects against T1D development. In T cells of NOD mice and T1D patients, UTX ablation resulted in the accumulation of CD8+ progenitor cells with concomitant deficiency of effectors, suggesting a key role for UTX in poising progenitors for transition to effectors. Mechanistically, UTXs role in T1D was independent of its inherent histone demethylase activity but instead relied on binding with transcription factors (TCF1 and STAT3) to co-regulate genes important in the maintenance and differentiation of progenitor CD8+ T cells. Together, these findings identify a critical role for UTX in T1D and the UTX:TCF1:STAT3 complex as a therapeutic target for terminating the long-lived autoimmune response.

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↗

bioRxiv2024

A pathologically expanded, clonal lineage of IL-21 producing CD4+ T cells drives Inflammatory neuropathy

Inflammatory neuropathies, which include CIDP (chronic inflammatory demyelinating polyneuropathy) and GBS (Guillain Barre Syndrome), result from autoimmune destruction of the peripheral nervous system (PNS) and are characterized by progressive weakness and sensory loss. CD4+ T cells play a key role in the autoimmune destruction of the PNS. Yet, key properties of pathogenic CD4+ T cells remain incompletely understood. Here, we use paired scRNAseq and scTCRseq of peripheral nerves from an inflammatory neuropathy mouse model to identify IL-21 expressing CD4+ T cells that are clonally expanded and multifunctional. These IL-21-expressing CD4+ T cells are comprised of two transcriptionally distinct expanded populations, which express genes associated with Tfh and Tph subsets. Remarkably, TCR clonotypes are shared between these two IL-21-expressing populations, suggesting a common lineage differentiation pathway. Finally, we demonstrate that IL-21 signaling is required for neuropathy development and pathogenic T cell infiltration into peripheral nerves. IL-21 signaling upregulates CXCR6, a chemokine receptor that promotes CD4+ T cell localization in peripheral nerves. Together, these findings point to IL-21 signaling, Tfh/Tph differentiation, and CXCR6-mediated cellular localization as potential therapeutic targets in inflammatory neuropathies.

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

Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors.

The mechanism by which ICI (immune checkpoint inhibitor) induce durable antitumor T cell activity remains inadequately defined. Tumors from melanoma patients who responded to ICI or MAPK pathway inhibitors (MAPKi) therapy generally displayed increased T cell infiltration and interferon gamma (IFN{gamma}) pathway activation. Yet, the rate of durable tumor control after ICI is almost twice that of MAPKi. Comparing the transcriptome of cohorts of melanoma patients treated with ICI or MAPKi therapy, we discovered that response to ICI is associated with CXCL13-driven recruitment of CXCR5+ B cells with higher clonal diversity than MAPKi. Higher B cell receptor (BCR) diversity allows presentation of diverse tumor antigens by B cells, resulting in robust increases of IFN{gamma} pathway activity and CXCL13 expression in tumor reactive CD8 T cells after ICI therapy. Accordingly, ICI-treated melanoma patients, but not MAPKi, whose tumors displayed higher BCR diversity and IFN{gamma} pathway score, survived significantly longer than those with either one or none. Thus, response to ICI, but not to MAPKi therapy, induces the recruitment of clonally diverse antigen presenting B cells that activate tumor specific, cytotoxic CD8 T cells to effect a durable antitumor immune response. Our result suggests that enhancing B cells tumor antigen presentation to intratumoral CD8 T cells can increase the rate of long-term response to ICI therapy.

cancer biology↗

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↗