Eomes cannot replace its paralog T-bet during expansion and differentiation of CD8 effector T cells

Autor: Christoph S. N. Klose, Tamara Kögl, Michael Köttgen, Jonas Fixemer, Sebastian J. Arnold, Frederic Arnold, Kristoffer Weissert, Alexis Hofherr, Yakup Tanriver, Peter Aichele, Jonas F. Hummel
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Fetal Proteins
Physiology
Cellular differentiation
CD8-Positive T-Lymphocytes
Immune Receptors
Biochemistry
White Blood Cells
Spectrum Analysis Techniques
Animal Cells
Immune Physiology
Medicine and Health Sciences
Cytotoxic T cell
Biology (General)
Cells
Cultured
Staining
0303 health sciences
Innate Immune System
Immune System Proteins
Effector
T Cells
030302 biochemistry & molecular biology
Cell Staining
Cell Differentiation
hemic and immune systems
Flow Cytometry
Cell biology
Spectrophotometry
Cytokines
Cytophotometry
Cellular Types
Research Article
Signal Transduction
QH301-705.5
Immune Cells
Immunology
Eomesodermin
Cytotoxic T cells
Mice
Transgenic
chemical and pharmacologic phenomena
Biology
Lymphocytic choriomeningitis
Research and Analysis Methods
Microbiology
03 medical and health sciences
Interferon-gamma
Virology
Genetics
medicine
Animals
T Helper Cells
Molecular Biology
Transcription factor
030304 developmental biology
Cell Proliferation
Blood Cells
Biology and Life Sciences
Proteins
Cell Biology
Molecular Development
RC581-607
medicine.disease
T Cell Receptors
CTL
Gene Expression Regulation
Specimen Preparation and Treatment
Immune System
Parasitology
Immunologic diseases. Allergy
T-Box Domain Proteins
CD8
Developmental Biology
Zdroj: PLoS Pathogens, Vol 16, Iss 9, p e1008870 (2020)
PLoS Pathogens
PLOS Pathogens
ISSN: 1553-7374
1553-7366
Popis: The two T-box transcription factors T-bet and Eomesodermin (Eomes) are important regulators of cytotoxic lymphocytes (CTLs), such as activated CD8 T cells, which are essential in the fight against intracellular pathogens and tumors. Both transcription factors share a great degree of homology based on sequence analysis and as a result exert partial functional redundancy during viral infection. However, the actual degree of redundancy between T-bet and Eomes remains a matter of debate and is further confounded by their distinct spatiotemporal expression pattern in activated CD8 T cells. To directly investigate the functional overlap of these transcription factors, we generated a new mouse model in which Eomes expression is under the transcriptional control of the endogenous Tbx21 (encoding for T-bet) locus. Applying this model, we demonstrate that the induction of Eomes in lieu of T-bet cannot rescue T-bet deficiency in CD8 T cells during acute lymphocytic choriomeningitis virus (LCMV) infection. We found that the expression of Eomes instead of T-bet was not sufficient for early cell expansion or effector cell differentiation. Finally, we show that imposed expression of Eomes after acute viral infection promotes some features of exhaustion but must act in concert with other factors during chronic viral infection to establish all hallmarks of exhaustion. In summary, our results clearly underline the importance of T-bet in guiding canonical CTL development during acute viral infections.
Author summary According to the World Health Organization infectious diseases kill over 17 million people per year. At the same time highly infectious viral diseases, such as Ebola and COVID-19 that are lacking specific treatments, are emerging to pose additional threats. It is therefore pivotal to precisely understand how our immune system responds towards pathogens to develop new treatment options. Here we have investigated the role of two related molecules, named T-bet and Eomes, that guide the development and function of lymphocytes in their fight against intracellular pathogens. We specifically focused on cytotoxic lymphocytes as these cells dominate the early phase of viral containment. We show that T-bet is essential for the expansion of cytotoxic lymphocytes and equip lymphocytes with the ability to efficiently eliminate virus-infected cells. Hence, our study provides new insights into the importance and specific actions of T-bet during acute viral infections and how this might be harnessed for future therapeutic interventions.
Databáze: OpenAIRE
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