Differential Nr4a1 and Nr4a3 expression discriminates tonic from activated TCR signalling events in vivo
| Autor: | Emma K. Jennings, David Bending, Juan Carlos Yam-Puc, Graham Anderson, Shivani Kanabar, Masahiro Ono, Thomas A.E. Elliot, Kai-Michael Toellner, David C. Wraith, Natasha Thawait |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
biology Chemistry T cell Receptor expression T-cell receptor B-cell receptor NFAT Major histocompatibility complex Cell biology 03 medical and health sciences 0302 clinical medicine medicine.anatomical_structure 030220 oncology & carcinogenesis medicine biology.protein Receptor CD8 030304 developmental biology |
| DOI: | 10.1101/767566 |
| Popis: | SummaryNr4a receptors are activated by T cell receptor (TCR) and B cell receptor (BCR) signalling and play key roles in T cell differentiation and promoting T cell exhaustion. How TCR signalling pathways regulate Nr4a receptors and their sensitivities to different physiological types of TCR signalling (e.g. tonic versus activating) remains unknown. Here we utilise Nr4a1/Nur77-GFP and Nr4a3-Tocky mice to elucidate the signalling pathways that govern Nr4a receptor expression in CD4+ and CD8+ T cells. Our findings reveal that Nr4a1-3 are Src family kinase-dependent. Moreover, Nr4a2 and Nr4a3 are abolished by calcineurin inhibitors and bind NFAT1, highlighting a necessary and sufficient role for NFAT in the control of Nr4a2 and Nr4a3, but redundancy for NFAT for Nr4a1. During T cell development, Nr4a1 is activated by tonic signalling during TCR-beta selection in the thymus, whilst Nr4a3 requires cognate peptide:MHC interactions for expression. Thus, due to differential sensitivity of Nr4a1 and Nr4a3 to TCR signalling pathways, T cells undergoing tonic versus activating TCR signalling events can be distinguished in vivo. |
| Databáze: | OpenAIRE |
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