ERK Signaling Controls Innate-like CD8+ T Cell Differentiation via the ELK4 (SAP-1) and ELK1 Transcription Factors

Abstract

In mouse thymocyte development, signaling by the TCR through the ERK pathway is required for positive selection of conventional naive T cells. The Ets transcription factor ELK4 (SAP-1), an ERK-regulated cofactor of the SRF transcription factor, plays an important role in positive selection by activating immediate-early genes such as the Egr transcription factor family. The role of ELK4–SRF signaling in development of other T cell types dependent on ERK signaling has been unclear. In this article, we show that ELK4, and its close relative ELK1, act cell autonomously in the thymus to control the generation of innate-like αβ CD8+ T cells with memory-like characteristics. Mice lacking ELK4 and ELK1 develop increased numbers of innate-like αβ CD8+ T cells, which populate the periphery. These cells develop cell autonomously rather than through expansion of PLZF+ thymocytes and concomitantly increased IL-4 signaling. Their development is associated with reduced TCR-mediated activation of ELK4–SRF target genes and can be partially suppressed by overexpression of the ELK4–SRF target gene EGR2. Consistent with this, partial inhibition of ERK signaling in peripheral CD8+T cells promotes the generation of cells with innate-like characteristics. These data establish that low-level ERK signaling through ELK4 (and ELK1) promotes innate-like αβ CD8+ T cell differentiation, tuning conventional versus innate-like development.

CXXC finger protein 4 inhibits the CDK18‐ERK1/2 axis to suppress the immune escape of gastric cancer cells with involvement of ELK1/MIR100HG pathway

“…For example, ERK/ELK1‐mediated BTB and CNC homolog 2 (Bach1) repression can control the differentiation of human naïve B cells 28 . Innate‐like CD8+ T cell differentiation can be promoted by low‐level ERK signalling through ELK1 and ELK4 11 . Phosphorylation of ERK indicates the activation of the MAPK axis, which can further phosphorylate the EKL1 protein.…”

“…ELK1 is a transcription factor binding to purine‐rich DNA sequences and has been shown to be up‐regulated in various cancers 10 . ELK1 may contribute to CD8+ T cell differentiation by activating the extracellular regulated protein kinases (ERK); this may help eradicate cancer cells by activating T cells 11 . However, the relationship between CXXC4 and ELK1 in gastric cancer is not clear.…”

Pioglitazone-Mediated Attenuation of Experimental Colitis Relies on Cleaving of Annexin A1 Released by Macrophages

“…As to further elucidate how AnxA1 could influence the anti-inflammatory effects of pioglitazone, we investigated whether AnxA1 knockdown of RAW 264.7 macrophages could affect pioglitazone-induced phosphorylation of extracellular regulator kinase (ERK). ERK is a signaling factor linked to several cell processes, such as cell survival, differentiation and migration, among others ( Maurice et al, 2018 ; Li et al, 2019 ; Zhou et al, 2019 ), and it is known that pioglitazone can activate ERK1/2 phosphorylation leading to anti-inflammatory effects, as reported on ischemic cardiomyocytes and on different cell lines, including colon cell lines ( Wang et al, 2012 ; Kole et al, 2016 ). Our data showed that pioglitazone did cause ERK phosphorylation, but such effect was not seen in AnxA1 knockdown cells, evidencing AnxA1 is required for pioglitazone-induced ERK phosphorylation to occur.…”

Langerhans cells immunocompetency is critical for IDO1-dependent ability to induce tolerogenic T cells

“…This is in concordance with the current understanding of gene transcription regulation, and highlights the importance of tolerance for LCs. While IRF4 51,52 , KLF6 53 RELB 54,55 , and ELK1 56 have been previously implicated in regulation of immunity or tolerance, HMGN3 binds to nucleosomes and regultes chromatin organisation 57 . Implication of its function in LCs are certainly intriguing, and warrant further detailed investigations.…”