EOMES interacts with RUNX3 and BRG1 to promote innate memory cell formation through epigenetic reprogramming

Nicolas Istaces,François Fuks,Séverine Thomas,Younes Achouri,Emilie Calonne,Muriel Nguyen,Viviana Lima Silva,Aurore Le,Matthieu Defrance,Abdulkader Azouz,Stanislas Goriely,Marion Splittgerber

doi:10.1038/s41467-019-11233-6

Nicolas Istaces, François Fuks + Show 10 more

Open Access

https://doi.org/10.1038/s41467-019-11233-6

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Abstract

Memory CD8+ T cells have the ability to provide lifelong immunity against pathogens. Although memory features generally arise after challenge with a foreign antigen, naïve CD8 single positive (SP) thymocytes may acquire phenotypic and functional characteristics of memory cells in response to cytokines such as interleukin-4. This process is associated with the induction of the T-box transcription factor Eomesodermin (EOMES). However, the underlying molecular mechanisms remain ill-defined. Using epigenomic profiling, we show that these innate memory CD8SP cells acquire only a portion of the active enhancer repertoire of conventional memory cells. This reprograming is secondary to EOMES recruitment, mostly to RUNX3-bound enhancers. Furthermore, EOMES is found within chromatin-associated complexes containing BRG1 and promotes the recruitment of this chromatin remodelling factor. Also, the in vivo acquisition of EOMES-dependent program is BRG1-dependent. In conclusion, our results support a strong epigenetic basis for the EOMES-driven establishment of CD8+ T cell innate memory program.

Highlights

Memory CD8+ T cells have the ability to provide lifelong immunity against pathogens
In order to further define the phenotypic status of TIM cells in WT Balb/c mice, we first looked at the expression of cell markers in EOMESlo or EOMEShi CD3+CD8SP thymocytes (Fig. 1a)
In order to identify the dependency of these cell subsets on IL-4/STAT6 and Type I IFNs/ISGF3 pathways shown to be required for their development[22], we compared the cell frequencies of these cell subsets between WT, Stat6-deficient, Il4deficient, and Irf9-deficient Balb/c mice (Fig. 1c)

Summary

Introduction

Memory features generally arise after challenge with a foreign antigen, naïve CD8 single positive (SP) thymocytes may acquire phenotypic and functional characteristics of memory cells in response to cytokines such as interleukin-4 This process is associated with the induction of the T-box transcription factor Eomesodermin (EOMES). When naïve CD8+ T cells encounter their cognate antigen (Ag) in secondary lymphoid organs and expand, most daughter cells undergo terminal differentiation into effector cells while a small fraction will form long-lived memory and persist after pathogen clearance[1] Such memory cells are epigenetically programmed through highly dynamic changes in enhancer repertoires and regulatory circuits for more rapid and effective responses upon re-stimulation with their Ag or inflammatory cytokines[2,3]. TIM cells represent a significant proportion of CD8SP thymocytes in wildtype (WT) Balb/c mice as thymic PLZF+ NKT cells producing IL-4 are physiologically abundant in this strain[13]

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