Biology subjects

Grau, M.

Publications and source records attributed to Grau, M..

4 recordsLinked to original sources

bioRxiv2024

Memory-Phenotype Ly49+ CD8 T emerging from the thymus develop into two subsets with distinct immune functions

Ly49+ CD8 T cells are memory-phenotype (MP) cells expressing Ly49 family inhibitory receptors, that control autoimmune diseases development through the regulation of follicular CD4 T cells. During viral infection, their number increases, suggesting an involvement in antiviral responses. These cells do not derive from naive cells and are thought to develop in the thymus. This study identified two subsets of Ly49+ CD8 T cells, based on CD8{beta} expression, in mice and humans. Lineage tracing and reliance on the transcription factor Zeb1 indicate a thymic origin via agonist selection. scRNAseq analysis revealed that a small fraction of CD8{beta}-Ly49+ cells acquired an effector profile during vaccinia virus infection. Moreover, the majority of Ly49+ CD8 T cells seems to respond to cytokine-driven bystander signals. In vitro, these signals promoted the expression of effector molecules such as IFN{gamma} and granzyme B, as well as the homing chemokine receptor CXCR5, potentially driving their recruitment to germinal centers. SummaryThis study shows that Ly49+ CD8 T cells comprises two subsets that develop in the thymus through agonist selection. In viral infection, both subsets respond to bystander stimuli that could drive their regulatory activity. Furthermore, some CD8{beta}-expressing Ly49+ cells exert TCR-mediated antiviral response.

immunology↗

bioRxiv2022

A new type of transcriptional reprogramming by an IRF4 mutation in lymphoma

SUMMARY PARAGRAPHDisease-causing mutations in genes encoding transcription factors (TFs) are a recurrent finding in hematopoietic malignancies and might involve key regulators of lineage adherence and cellular differentiation1-3. Such mutations can affect TF-interactions with their cognate DNA-binding motifs4, 5. Whether and how TF-mutations impact upon the nature of binding to TF composite elements (CE) and influence their interaction with other TFs is unclear. Here, we report a new mechanism of TF alteration in human lymphomas with perturbed B cell identity. It is caused by a recurrent somatic missense mutation c.295T>C (p.Cys99Arg; p.C99R) targeting the center of the DNA-binding domain of Interferon Regulatory Factor 4 (IRF4), a key TF in immune cell-differentiation and -activation6, 7. IRF4-C99R fundamentally alters IRF4 DNA-binding, with loss-of-binding to canonical IRF motifs and neomorphic gain-of-binding to canonical and non-canonical IRF composite elements (CEs). Furthermore, IRF4-C99R thoroughly modifies IRF4 function, by blocking IRF4-dependent plasma cell induction, and up-regulating disease-specific genes in a non-canonical Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner. Our data explain how a single arginine mutation creates a complex switch of TF specificity and gene regulation. These data open the possibility of designing specific inhibitors to block the neomorphic, disease-causing DNA-binding activities of a mutant transcription factor.

cancer biology↗

bioRxiv2020

Mutational dynamics and transmission properties of SARS-CoV-2 superspreading events in Austria

Superspreading events shape the COVID-19 pandemic. Here we provide a national-scale analysis of SARS-CoV-2 outbreaks in Austria, a country that played a major role for virus transmission across Europe and beyond. Capitalizing on a national epidemiological surveillance system, we performed deep whole-genome sequencing of virus isolates from 576 samples to cover major Austrian SARS-CoV-2 clusters. Our data chart a map of early viral spreading in Europe, including the path from low-frequency mutations to fixation. Detailed epidemiological surveys enabled us to calculate the effective SARS-CoV-2 population bottlenecks during transmission and unveil time-resolved intra-patient viral quasispecies dynamics. This study demonstrates the power of integrating deep viral genome sequencing and epidemiological data to better understand how SARS-CoV-2 spreads through populations. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

microbiology↗

bioRxiv2017

Antigen-induced but not innate memory CD8 T cells express NKG2D and are recruited to the lung parenchyma upon viral infection

The pool of memory-phenotype CD8 T cells is composed of antigen-induced (AI) and cytokine-induced innate (IN) cells. IN have been described as having similar properties to AI memory cells. However, we found that pathogen-induced AI memory cells can be distinguished from naturally-generated IN memory cells by surface expression of NKG2D. Using this marker, we described the increased functionalities of AI and IN memory CD8 T cells compared to naive cells, as shown by comprehensive analysis of cytokine secretion and gene expression. However, AI differed from IN memory CD8 T cells by their capacity to migrate to the lung parenchyma upon inflammation or infection, a process dependent on their expression of ITGA1/CD49a and ITGA4/CD49d integrins.

immunology↗