Biology subjects

Moudra, A.

Publications and source records attributed to Moudra, A..

5 recordsLinked to original sources

bioRxiv2026

Distinct activation programs in naive and memory CD8 T cells govern stemness and effector persistence of their progeny

Infection- and vaccination-induced memory CD8+ T cells provide protection upon subsequent exposure to cognate antigen through their increased abundance and robust per-cell responses. However, how prior antigen experience alters T-cell activation programs remains poorly understood. We longitudinally profiled gene expression in naive, central memory, and effector memory CD8+ T cells in response to cognate antigen across multiple models of acute infection. Naive T cells engaged TOX- and TCF7-centered programs and generated early stem-like central memory precursors. Their initially slow proliferation was followed by rapid expansion and the production of large numbers of short-lived effector cells. Central memory T cells rapidly triggered effector and proliferation programs while maintaining a smaller self-renewing population. Effector memory T cells expanded poorly and generated almost exclusively effector progeny. Effector progeny derived from both memory subsets survived contraction more efficiently than naive T-cell-derived progeny and established persistent effector memory populations. These data show that prior antigen experience does not simply accelerate CD8+ T-cell activation but redirects cell-intrinsic programs that shape progeny fate and persistence. These distinct programs may reflect adaptation to primary versus repeated antigen exposure and suggest that infection and vaccination history can shape the balance between stem-like memory and persistent effector populations.

immunology↗

bioRxiv2023

Investigating the effects of radiation, T cell depletion, and bone marrow transplantation on murine gut microbiota

Microbiome research has gained much attention in recent years as the importance of gut microbiota in regulating host health becomes increasingly evident. However, the impact of radiation on the microbiota in the murine bone marrow transplantation model is still poorly understood. In this paper, we present the major conclusions of our investigation into the effects of radiation and subsequent bone marrow transplantation with or without T cell depletion of the donor bone-marrow on the microbiota of the ileum and cecum. Our findings show that radiation has different effects on the microbiota of the two intestinal regions, with the cecum showing increased interindividual variation, suggesting an impaired ability of the host to regulate microbial symbionts, consistent with the Anna Karenina principle. Additionally, we observed changes in the ileum composition, including an increase in bacterial taxa that are important modulators of host health, such as Akkermansia and Faecalibaculum. In contrast, radiation in the cecum was associated with an increased abundance of several common commensal taxa in the gut, including Lachnospiraceae and Bacteroides. Finally, we found that high doses of radiation had more substantial effects on the caecal microbiota of the T-cell-depleted group than that of the non-T-cell-depleted group. Overall, our results contribute to a better understanding of the complex relationship between radiation and the gut microbiota in the context of bone marrow transplantation and highlight the importance of considering different intestinal regions when studying microbiome responses to environmental stressors.

immunology↗

bioRxiv2020

Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits

Interleukin 2 (IL-2) is a key homeostatic cytokine, with potential therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical application has been hampered by pleiotropic functionality and wide-spread receptor expression, with unexpected adverse events during trials. To characterize the IL-2 homeostatic network, we developed a novel mouse strain allowing IL-2 production to be diverted. Rewiring of IL-2 production to diverse leukocyte sources allowed the identification of contextual influences over IL-2 impact. Network analysis identified a priority access for Tregs, and a competitive fitness cost induced among both Tregs and conventional CD4 T cells for IL-2 production. CD8 T cells and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified the Treg circuit, while IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+ Tregs and ILC2 cells. The former was associated with an unexpected concentration of rare CD8+ Tregs in B cell zones, while the latter drove a downstream, IL-5-mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain unexpected adverse effects observed during clinical trials of exogenous IL-2. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability. Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

immunology↗

bioRxiv2020

Phenotypic and clonal stability of antigen-inexperienced memory-like T cells across the genetic background, hygienic status, and aging

Antigen-inexperienced memory-like T (AIMT) cells are functionally unique T cells representing one of the two largest subsets of murine CD8+ T cells. However, differences between laboratory inbred strains, insufficient data from germ-free mice, a complete lack of data from feral mice, and unclear relationship between AIMT cells formation during aging represent major barriers for better understanding of their biology. We performed a thorough characterization of AIMT cells from mice of different genetic background, age, and hygienic status by flow cytometry and multi-omics approaches including analyses of gene expression, TCR repertoire, and microbial colonization. Our data showed that AIMT cells are steadily present in mice independently of their genetic background and hygienic status. Despite differences in their gene expression profiles, young and aged AIMT cells originate from identical clones. We identified that CD122 discriminates two major subsets of AIMT cells in a strain-independent manner. Whereas thymic CD122LOW AIMT cells (innate memory) prevail only in young animals with high thymic IL-4 production, peripheral CD122HIGH AIMT cells (virtual memory) dominate in aged mice. Co-housing with feral mice changed the bacterial colonization of laboratory strains, but had only minimal effects on the CD8+ T-cell compartment including AIMT cells.

immunology↗

bioRxiv2017

Strong homeostatic TCR signals induce formation of self-tolerant virtual memory CD8 T cells

Virtual memory T cells are foreign antigen-inexperienced T cells that have acquired memory-like phenotype and constitute for 10-20% of all peripheral CD8+ T cells in mice. Their origin, biological roles, and relationship to naive and foreign antigen-experienced memory T cells are incompletely understood. By analyzing TCR repertoires and using retrogenic monoclonal T-cell populations, we show that virtual memory T cells originate exclusively from strongly self-reactive T cells. Moreover, we show that the stoichiometry of the CD8 interaction with Lck regulates the size of the virtual memory T-cell compartment via modulating the self-reactivity of individual T-cell clones. We propose a so far unappreciated peripheral T-cell fate decision checkpoint that eventually leads to the differentiation of highly self-reactive T cells into virtual memory T cells. This underlines the importance of the variable level of self-reactivity in polyclonal T cells for the generation of functional T-cell diversity. Although virtual memory T cells descend from the highly self-reactive clones and acquire a partial memory program, they do not show higher capacity to induce autoimmune diabetes than naive T cells. Thus, virtual memory T cells are not generally more responsive than naive T cells, because their activity highly depends on the immunological context.\n\nSummaryWe conclude that virtual memory T cells are formed from self-reactive CD8+ T cells in a process regulated by CD8-Lck stoichiometry. Despite their self-reactivity and partial memory differentiation program, virtual memory T cells did not show a strong autoimmune potential.

immunology↗