Deciphering the role of the MARK2 kinase in T cell activation - Archive ouverte HAL Access content directly
Conference Papers Year :

Deciphering the role of the MARK2 kinase in T cell activation

, , (1, 2) , , ,
1
2
Hermine Ferran
  • Function : Author
Stephanie Dogniaux
  • Function : Author
Théo Cools
  • Function : Author
Claire L Hivroz
Laurence Ardouin-Bataille
  • Function : Author

Abstract

T cell activation occurs following the TCR recognition of an antigenic peptide presented by an APC. The formation of a tightly organized contact between the two cells, the Immune Synapse (IS) ensures both T cell activation and the polarized delivery of cytokines or lytic granules from the T cell directly to the target cell. The IS is the site of intense endocytosis and exocytosis of signaling molecules involved in proper T cell activation. However, the exact role of this intense traffic and the mechanisms involved in its regulation are still unknown. Our laboratory has been studying the intracellular traffic of LAT an adaptor protein involved in TCR stimulation and present at the plasma membrane and in intracellular vesicles. We have shown that upon T cell activation LAT follows an endocytic pathway which is absolutely necessary for full T cell activation. In an attempt to characterize which molecules could regulate the trafficking of LAT vesicles, we have identified the serine-threonine kinase Par1b/MARK2. MARK2 was shown in the literature to be important for the establishment and maintenance of cell polarity by phosphorylating the microtubule-associated proteins (MAPs) that regulate microtubule stability. However, the vast majority of the work published on MARK2 was done in fibroblasts, epithelial cells and/or neuronal cells and the role of MARK2 was poorly studied in T lymphocytes. Using proteomics analysis, we identified proteins interacting with MARK2 in Jurkat T cells. We found interactors involved in the regulation of several pathways as different as cellular trafficking (Sec16A), microtubules organization (CLASP1, NEDD1……) or transcriptional repression (HDAC7). Thus it seems that in T lymphocytes MARK2 could be involved in multiple pathways. To decipher the role of MARK2 in the regulation of T cell activation in vivo we have generated conditional KO mice deprived of MARK2 only in T cells (MARK2 cKO). Our data show that MARK2 cKO mice have hyper-activated lymphocytes and therefore develop signs of autoimmunity characterized by the presence of anti-DNA antibodies and of immune infiltrates in multiple organs. In vitro, TCR activated MARK2 cKO T cells produce more cytokines than the WT cells. A transcriptomic analysis of naïve CD4+ T cells from WT or MARK2 cKO mice, activated in vitro through the TCR, revealed that the vast majority of upregulated genes in MARK2 cKO T cells belong to the IFN type I pathway. Our working hypothesis is that in absence of MARK2, the signal received by T cells is not properly regulated leading to an over-activation of the naïve CD4+ T cells, more IFN related genes and eventually to the development of auto-immunity. Collectively our results suggest that MARK2 is a negative regulator of T cell activation showing a new role for this kinase in the control of the homeostasis of the immune system.
Not file

Dates and versions

hal-03866261 , version 1 (22-11-2022)

Identifiers

  • HAL Id : hal-03866261 , version 1

Cite

Hermine Ferran, Stephanie Dogniaux, Elise Brisebard, Théo Cools, Claire L Hivroz, et al.. Deciphering the role of the MARK2 kinase in T cell activation. EMBO Workshop: Lymphocyte antigen receptor signaling, May 2022, Siena, Italy, Italy. ⟨hal-03866261⟩

Collections

UNAM INRAE
0 View
0 Download

Share

Gmail Facebook Twitter LinkedIn More