Biology subjects

Stier, M. T.

Publications and source records attributed to Stier, M. T..

4 recordsLinked to original sources

bioRxiv2026

SAP loss limits anti-insulin atypical B cell activation and pro-inflammatory CD8 T cells despite preserved Tfh responses to protect against type 1 diabetes

SLAM-associated protein (SAP) is required for T follicular helper (Tfh)-B cell interactions that underlie germinal center formation, but it is unclear if SAP governs islet-reactive CD4+ T cell-B cell interactions and downstream pro-inflammatory CD8+ T cell destruction of islets in type 1 diabetes (T1D). To address this question, we utilized the VH125SD.NOD mouse model, whereby 1-3% of all B cells bind insulin. Germline SAP loss in this model led to reduced T1D incidence and impaired germinal center B cell formation, yet did not alter T follicular helper cell formation or phenotype. SAP loss reduced pro-inflammatory and activated insulin-autoreactive B-T interactions and limited anti-insulin B cell proliferation, activation, and upregulation of co-stimulatory molecules otherwise enhanced in the pancreas. Anti-insulin extrafollicular antibody and memory responses following immunization were preserved in VH125SD.SAP-/-.NOD mice, but activated atypical anti-insulin B cell responses were reduced. Ultimately, SAP loss led to reduced pro-inflammatory CD8+ T cell formation and islet-reactive progenitor exhausted CD8+ T cells in pancreata. These data highlight the essential role of SAP in mediating proinflammatory, anti-insulin B-T interactions to support T1D. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/741363v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1971e3borg.highwire.dtl.DTLVardef@41d72eorg.highwire.dtl.DTLVardef@963004org.highwire.dtl.DTLVardef@2a76b5_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Critical illness expands a transcriptionally distinct hypometabolic CD8+ T effector program associated with respiratory failure and mortality

Immune dysfunction is a major driver of morbidity and mortality in critical illness syndromes including sepsis. Specifically, CD8+ T cell dysfunction has been linked to organ failure and death. To characterize the immune substructure of circulating CD8+ T cells in critical illness at high dimension, we used single-cell RNA sequencing of peripheral blood CD8+ T cells from 38 critically ill patients and 9 healthy controls. We annotated seven CD8+ T cell clusters, which included a CD8+ effector subset, termed T effector state 2 (TEff-2), that was only present in critically ill patients and associated with more severe respiratory failure and higher mortality. TEff-2 showed effector activation and inflammatory stress conditioning yet had markedly reduced metabolic transcripts without canonical features of exhaustion. Trajectory analyses positioned TEff-2 as a terminal CD8+ T effector cell fate driven in part by DDIT4 and DUSP1, which negatively regulate mTOR and MAPK signaling, respectively. Interestingly, this transcriptional program was indistinguishable by classical protein cytometry methods. These results, including the mortality association, were validated in a larger (n=91) independent external cohort of critically ill patients with sepsis. In summary, TEff-2 represents a latent transcriptional program that delineates a clinically high-risk CD8+ T cell state in critical illness.

immunology↗

bioRxiv2025

Metabolic Adaptations Rewire CD4 T Cells in a Subset-Specific Manner in Human Critical Illness with and without Sepsis

Host immunity in sepsis has features of hyperinflammation together with progressive immunosuppression, particularly among CD4 T cells, that can predispose to secondary infections and ineffectual organ recovery. Metabolic and immunologic dysfunction are archetypal findings in critically ill patients with sepsis, but whether these factors are mechanistically linked remains incompletely defined. We characterized functional metabolic properties of human CD4 T cells from critically ill patients with and without sepsis and healthy adults. CD4 T cells in critical illness showed increased subset-specific metabolic plasticity, with regulatory T cells (Tregs) acquiring glycolytic capacity that stabilized suppressive markers FOXP3 and TIGIT and correlated with clinical illness severity. Single-cell transcriptomics identified differential kynurenine metabolism in Tregs, which was validated ex vivo as a mechanism of Treg glycolytic adaptation and suppressive rewiring. These findings underscore immunometabolic dysfunction as a driver of CD4 T cell remodeling in sepsis and suggest therapeutic avenues to restore an effective immune response.

immunology↗

bioRxiv2023

Androgen Signaling Restricts Glutaminolysis to Drive Sex-Specific Th17 Metabolism

Females have increased prevalence of many Th17-mediated diseases. While androgen signaling decreases Th17-mediated inflammation, the mechanisms are not fully understood. Th17 cells rely on glutaminolysis; however, it remains unclear whether androgen receptor (AR) signaling in males modifies glutamine metabolism to suppress Th17-mediated inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared to females, and AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis. Using allergen-induced airway inflammation models, we determined females, but not males, had a critical reliance upon glutaminolysis for Th17-mediated airway inflammation, and AR signaling attenuated glutamine uptake by reducing expression of glutamine transporters. These findings were confirmed in circulating human Th17 cells with minimal reliance on glutamine uptake in male compared to female Th17 cells. We found that AR signaling attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for design and implementation of Th17 or glutaminolysis targeted therapeutics. HighlightsO_LIHuman male CD4+ T cells have decreased expression of metabolic enzymes and decreased reliance on glutaminolysis compared to female CD4+ T cells. C_LIO_LIAndrogen signaling decreased mitochondrial metabolism in Th17 cells and decreased airway inflammation. C_LIO_LIAndrogen signaling decreased glutamine uptake and utilization in Th17 cells. C_LI

immunology↗