Biology subjects

Schaefer, L.

Publications and source records attributed to Schaefer, L..

4 recordsLinked to original sources

bioRxiv2026

Mechanisms of CD4+ T tolerance to a corneal epithelial neoantigen

Tissue-specific peripheral tolerance mechanisms are essential to prevent autoimmunity. The cornea is immune privileged, and anterior chamber-associated immune deviation (ACAID) governs its inner surface. However, the mechanisms that apply to corneal epithelial (outer surface) antigens remain unknown. Using an inducible, cornea-restricted neoantigen mouse model, we found that the cornea relies on inducible regulatory T cells (Tregs) rather than ignorance or ACAID for its epithelial antigens. Although the cornea is both avascular and alymphatic, its epithelial antigens are still efficiently presented by ocular surface-derived antigen-presenting cells to T cells in draining lymph nodes under homeostatic conditions, leading to conventional antigen-specific Treg expansion without ocular pathology. This tolerance was not absolute: systemic immunization redirected antigen-specific responses toward pathogenic effector T cells that disrupted epithelial barrier function. These findings identify Treg induction as a dominant mechanism of corneal epithelial immune homeostasis and demonstrate that inflammatory priming can render a tolerated corneal antigen into an autoimmune target, providing mechanistic insight into dry eye pathogenesis. SummaryThis study shows that immune tolerance to corneal epithelial neoantigens relies not on immune privilege but on peripherally induced regulatory T cells in the draining lymph nodes that can be subverted by innate activation, shedding light on ocular surface disease pathophysiology.

immunology↗

bioRxiv2026

Autoimmune CD4+T cells Cause Meibomian Gland Dysfunction

Sjogren disease (SjD) is an autoimmune disease driven by autoreactive CD4+T cells that leads to an immune-mediated loss of lacrimal glands. Meibomian glands are lipid-producing glands in the eyelids that help prevent tear evaporation. While the role of T cells in lacrimal gland-mediated destruction is well established, it is unknown whether pathogenic T cells can cause MG dysfunction (MGD). Herein, we investigated whether autoreactive CD4+T cells induce MGD and characterized the pathophysiologic mechanisms using an adoptive transfer model. T cells were isolated from CD25KO (CD4KO) or wild-type (CD4WT) mice, transferred into Rag1KO mice. Further, CD4KO cells were co-adoptively transferred with WT regulatory T cells (CD4KO+TregsWT). Our results demonstrate that CD4KO recipients had MG dropout, CD4+IFN-{gamma}+ infiltration, increased MHC II presentation within the periglandular area, MG fibrosis, and decreased lipid production and upregulation of pathways related to inflammation, including Type II interferon signaling. Rag1KO, CD4WT, and CD4KO+TregsWT recipients exhibited minimal inflammation in the periglandular MG area. These results indicate that autoimmune CD4+T cells are sufficient to cause MGD, and healthy young regulatory T cells can prevent T-cell-mediated damage. Taken together, our findings provide mechanistic insights into the pathogenesis autoimmune SjD, and could impact how patients are managed in the clinic.

pathology↗

bioRxiv2025

Monocyte Dysregulation Defines an MDD-Specific Transcriptional Signature Closely Linked to Clinical MDD Traits

ObjectiveMajor depressive disorder (MDD) is a highly heterogeneous psychiatric condition contributing significantly to the global disease burden. In a subset of MDD patients inflammatory processes accompany the disease and this has also been reported for other psychiatric conditions like schizophrenia (SZ). However, little is known regarding immune deregulation in relation to clinical symptoms. MethodsCellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) of peripheral blood mononuclear cells (PBMCs) from patients with MDD (n=22), SZ (n=10), and healthy controls (HCs, n=26) was performed, yielding 633,284 high-quality single-cell profiles. Differential gene expression, cell composition, pathway enrichment, and weighted gene co-expression network analyses were conducted. MDD symptom severity was assessed using the Beck Depression Inventory-II (BDI-II), enabling the correlation of gene expression with individual disease symptoms. ResultsWe identified disease-specific transcriptomic signatures for MDD as well as for SZ and shared gene expression changes between the two conditions. For MDD, monocyte numbers were elevated concomitant with a strong enrichment of interferon signaling. The MDD-specific signature involving all peripheral cell types correlated strongly with key symptoms of depression like sadness or pessimism. Reactome analysis identified nuclear factor kappa-light-chain-enhancer of activated B cells (NF-{kappa}B)-associated pathways among the genes positively correlating with disease symptoms and traits. ConclusionOur findings might help to stratify psychiatric patients and provide a multidimensional framework for investigating immune contributions to psychiatric disorders and highlight potential targets for therapeutic intervention. Clinical symptoms might be reflected on a molecular level paving the way for more targeted and effective interventions.

genomics↗

bioRxiv2025

Protein dynamics affect O2-stability of Group B -hydrogenase from Thermosediminibacter oceani

In the pursuit of sustainable green energy generation, [FeFe]-hydrogenases have attracted significant attention due to their ability to catalyze hydrogen production. However, the sensitivity of these enzymes to O2 is a major obstacle for their application as biocatalysts in energy conversion technologies. In the search for an O2-stable [FeFe]-hydrogenase, we identified the hydrogenase ToHydA from Thermosediminibacter oceani that belongs to the rarely characterized Group B (M2a) [FeFe]-hydrogenases. Our findings demonstrate that ToHydA exhibits remarkable O2-stability, even under prolonged O2 exposure. By characterizing site-directed mutagenesis variants, we found that the highly conserved proton-transporting cysteine protects H-cluster from O2-induced degradation by forming Hinact state. The additional cysteine residue in the TSCCCP motif of ToHydA, a feature unique to Group B (M2a) [FeFe]-hydrogenases, enhances the flexibility of that motif and facilitates the formation of the Hinact state. Moreover, ToHydA possesses unique features, including the formation of an unusual Hinact resting state that distinguishes the enzyme from other [FeFe]-hydrogenases. Our atomistic molecular dynamics simulations reveal a previously unrecognized cluster of hydrophobic residues centered around the proton-transporting cysteine-bearing loop. This structural feature appears to be a common molecular characteristic in hydrogenases that form the O2-protected Hinact state. By exploiting these molecular features of ToHydA, future research can aim to rationally design hydrogenases that combine high catalytic activity with enhanced O2 stability, to develop more efficient and durable catalysts. Table of Contents Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/643706v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@96b4aorg.highwire.dtl.DTLVardef@62f367org.highwire.dtl.DTLVardef@59f170org.highwire.dtl.DTLVardef@fa2fd7_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗