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

PLoS Pathog. 2020 Sep 29;16(9):e1008870. doi: 10.1371/journal.ppat.1008870. eCollection 2020 Sep.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cell Differentiation / physiology*
  • Cell Proliferation
  • Cells, Cultured
  • Fetal Proteins / metabolism
  • Gene Expression Regulation / physiology
  • Interferon-gamma / metabolism
  • Mice, Transgenic
  • T-Box Domain Proteins / metabolism*

Substances

  • Eomes protein, mouse
  • Fetal Proteins
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Interferon-gamma
  • Brachyury protein

Grant support

The work was supported by grants from i) the German Research Foundation (DFG; https://www.dfg.de/): TA 436/4-1 and SFB 1160 (B08) to Y.T.; SFB1160 (B04) to P.A.; KL 2963/2-1 and KL 2963/3-1 (SPP 1937) to C.S.N.K.; AR 732/3-1 and AR 732/2-1 and SFB850 (A03) to S.J.A; TRR 152 (P03) – Project ID 239283807 to M.K.; under Germany´s Excellence Strategy – EXC-2189 – Project ID: 390939984 to M.K. and S.J.A, ii) the European Research Council Starting Grant (ERCEA; 803087 to C.S.N.K., https://erc.europa.eu/), iii) the Dr. Heinrich Kircher-Stiftung of the Albert-Ludwigs-University of Freiburg to J.F. (https://www.uni-freiburg.de/universitaet/foerdern-und-stiften/foerdervereine-stiftungen/stiftungen-des-stiftungsfonds/kircher-stiftung), iv) Berta-Ottenstein-Programme for Clinician Scientists, Faculty of Medicine, Albert-Ludwigs-University of Freiburg to F.A. (https://www.med.uni-freiburg.de/en/research/career-paths-and-qualification/bop) and v) Else Kröner-Fresenius Stiftung (https://www.ekfs.de/) to Y.T. (2017_EKES.34). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.