Biology subjects

Grotz, M.

Publications and source records attributed to Grotz, M..

3 recordsLinked to original sources

bioRxiv2026

DextraDemixer enables accurate identification of antigen-specific T cells from pMHC multimer experiments

Antigen specificity of T cells defines the adaptive immune response, yet the vast majority of known T cell receptors (TCRs) lack annotated antigen targets. Single-cell peptide-MHC (pMHC) multimer assays offer a scalable approach to map TCR-antigen interactions. Still, their utility is limited by pervasive non-specific binding and severe overlap between signal and noise, which confound the accurate identification of antigen-specific cells. To address these limitations, we present DextraDemixer, a Bayesian hierarchical mixture model that disentangles antigen-specific T cells from background noise in pMHC multimer data. The model integrates information from negative controls and clonotype structure while providing calibrated uncertainty estimates for classification. We further introduce a dynamic thresholding scheme that enables credible interval-bounded control of the false discovery rate. Extensive benchmarking on simulated datasets and antigen-specific spike-in experiments demonstrated the models robustness and improved accuracy over established methods. In a longitudinal SARS-CoV-2 vaccine study, DextraDemixer identified antigen-specific TCRs characterized by high sequence similarity, elevated antigen-specificity prediction scores, and strong clonal purity. Annotations showed high concordance with external validation data and supported the identification of antigen-specific motifs. Overall, DextraDemixer provides a principled probabilistic framework for reliable identification of antigen-specific TCRs from single-cell pMHC-multimer assays.

bioinformatics↗

bioRxiv2025

Oral L-arginine cures arginase 1-dependent chronic cutaneous leishmaniasis by redirecting the T helper cell response

Leishmania (L.) mexicana-induced cutaneous leishmaniasis (CL) is a neglected tropical disease characterized by localized chronic ulcers (LCL) and, in rare cases, by disseminated skin lesions (DCL). The therapeutic options for CL are currently limited, and the immune dysregulation leading to chronicity of disease is poorly understood. Here, we identified interleukin (IL)-10-dependent upregulation of arginase 1 (ARG1) in cutaneous CX3CR1+ myeloid cells as central immunometabolic determinant of chronic CL in L. mexicana-infected C57BL/6 wild-type (WT) mice. Deletion of Arg1 in myeloid cells (Arg1{Delta}Cx3cr1) enabled parasite control and clinical healing. Single-cell RNA sequencing revealed that ARG1, together with interferon-{gamma} produced by T-helper 1 (Th1) cells, caused pathologic differentiation of Ly6Chigh monocytes into inflammatory macrophages (iMACs) that simultaneously expressed ARG1, nitric oxide synthase type 2 (NOS2) and the chemokines CXCL9/10. These Arg1+Nos2+Cxcl9/10+iMACs induced a lasting depletion of L-arginine in the skin, served as parasite niche, and maintained a self-perpetuating cycle of host cell recruitment. In Arg1{Delta}Cx3cr1 mice, the ARG1+NOS2+ host cell niche for the parasite was diminished. Prophylactic or therapeutic oral L-arginine supplementation restored tissue arginine levels, reduced parasite burden, and prevented or resolved chronic disease. L-arginine-treated mice showed enhanced T cell expansion and Th1 differentiation, remained free of clinical relapses, and were resistant to reinfection. As skin lesion biopsies from L. mexicana-infected LCL and DCL patients demonstrated a similar pattern of Th1/Th2 cytokine, Arg1 and Nos2 mRNA expression as seen in mice, we suggest metabolic reprogramming by oral L-arginine as a promising and easy-to-apply host-directed therapy for human L. mexicana CL. ONE SENTENCE SUMMARYArginase 1-mediated arginine depletion accounts for chronic cutaneous leishmaniasis, which can be prevented and even cured by oral L-arginine therapy.

immunology↗

bioRxiv2024

Quality of vaccination-induced T cell responses is conveyed by polyclonality and high, but not maximum, antigen receptor avidity

While the quantity of vaccination-induced T cells represents a routine immunogenicity parameter, the quality of such responses is poorly understood. Here, we report on a clinical cohort of 29 human healthy individuals who received three mRNA vaccinations against SARS-CoV-2 before any breakthrough infection. We characterized the magnitude, phenotype and clonal composition of CD8 T cell responses against 16 epitope specificities by ELISpot, flow cytometry as well as single-cell RNA, TCR and surface protein sequencing. To test the functionality of identified clonotypes, 106 T cell receptors (TCR) from five epitope-specific repertoires were re-expressed and tested for peptide sensitivity. While recruited repertoires were overall enriched for high-avidity TCRs, differential clonal expansion was not linked to fine avidity differences. Instead, maintenance of polyclonality ensured robustness in counteracting mutational escape of epitopes. Our findings on the induction and maintenance of high-functionality polyclonal T cell repertoires shed light on T cell quality as a neglected criterion in the assessment of vaccine immunogenicity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/620795v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@f48079org.highwire.dtl.DTLVardef@1eaa46org.highwire.dtl.DTLVardef@13cfb93org.highwire.dtl.DTLVardef@a8a6e5_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗