Salt inducible kinases 2 and 3 are required for thymic T cell development

Abstract Salt Inducible Kinases (SIKs), of which there are 3 isoforms, are established to play roles in innate immunity, metabolic control and neuronal function, but their role in adaptive immunity is unknown. To address this gap, we used a combination of SIK knockout and kinase-inactive knock-in mi...

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Autores principales:	Meriam Nefla, Nicola J. Darling, Manuel van Gijsel Bonnello, Philip Cohen, J. Simon C. Arthur
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/612ab4473bc34e1f9a8c8690879295a3
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spelling	oai:doaj.org-article:612ab4473bc34e1f9a8c8690879295a32021-11-08T10:53:21ZSalt inducible kinases 2 and 3 are required for thymic T cell development10.1038/s41598-021-00986-02045-2322https://doaj.org/article/612ab4473bc34e1f9a8c8690879295a32021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-00986-0https://doaj.org/toc/2045-2322Abstract Salt Inducible Kinases (SIKs), of which there are 3 isoforms, are established to play roles in innate immunity, metabolic control and neuronal function, but their role in adaptive immunity is unknown. To address this gap, we used a combination of SIK knockout and kinase-inactive knock-in mice. The combined loss of SIK1 and SIK2 activity did not block T cell development. Conditional knockout of SIK3 in haemopoietic cells, driven by a Vav-iCre transgene, resulted in a moderate reduction in the numbers of peripheral T cells, but normal B cell numbers. Constitutive knockout of SIK2 combined with conditional knockout of SIK3 in the haemopoietic cells resulted in a severe reduction in peripheral T cells without reducing B cell number. A similar effect was seen when SIK3 deletion was driven via CD4-Cre transgene to delete at the DP stage of T cell development. Analysis of the SIK2/3 Vav-iCre mice showed that thymocyte number was greatly reduced, but development was not blocked completely as indicated by the presence of low numbers CD4 and CD8 single positive cells. SIK2 and SIK3 were not required for rearrangement of the TCRβ locus, or for low level cell surface expression of the TCR complex on the surface of CD4/CD8 double positive thymocytes. In the absence of both SIK2 and SIK3, progression to mature single positive cells was greatly reduced, suggesting a defect in negative and/or positive selection in the thymus. In agreement with an effect on negative selection, increased apoptosis was seen in thymic TCRbeta high/CD5 positive cells from SIK2/3 knockout mice. Together, these results show an important role for SIK2 and SIK3 in thymic T cell development.Meriam NeflaNicola J. DarlingManuel van Gijsel BonnelloPhilip CohenJ. Simon C. ArthurNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Meriam Nefla Nicola J. Darling Manuel van Gijsel Bonnello Philip Cohen J. Simon C. Arthur Salt inducible kinases 2 and 3 are required for thymic T cell development
description	Abstract Salt Inducible Kinases (SIKs), of which there are 3 isoforms, are established to play roles in innate immunity, metabolic control and neuronal function, but their role in adaptive immunity is unknown. To address this gap, we used a combination of SIK knockout and kinase-inactive knock-in mice. The combined loss of SIK1 and SIK2 activity did not block T cell development. Conditional knockout of SIK3 in haemopoietic cells, driven by a Vav-iCre transgene, resulted in a moderate reduction in the numbers of peripheral T cells, but normal B cell numbers. Constitutive knockout of SIK2 combined with conditional knockout of SIK3 in the haemopoietic cells resulted in a severe reduction in peripheral T cells without reducing B cell number. A similar effect was seen when SIK3 deletion was driven via CD4-Cre transgene to delete at the DP stage of T cell development. Analysis of the SIK2/3 Vav-iCre mice showed that thymocyte number was greatly reduced, but development was not blocked completely as indicated by the presence of low numbers CD4 and CD8 single positive cells. SIK2 and SIK3 were not required for rearrangement of the TCRβ locus, or for low level cell surface expression of the TCR complex on the surface of CD4/CD8 double positive thymocytes. In the absence of both SIK2 and SIK3, progression to mature single positive cells was greatly reduced, suggesting a defect in negative and/or positive selection in the thymus. In agreement with an effect on negative selection, increased apoptosis was seen in thymic TCRbeta high/CD5 positive cells from SIK2/3 knockout mice. Together, these results show an important role for SIK2 and SIK3 in thymic T cell development.
format	article
author	Meriam Nefla Nicola J. Darling Manuel van Gijsel Bonnello Philip Cohen J. Simon C. Arthur
author_facet	Meriam Nefla Nicola J. Darling Manuel van Gijsel Bonnello Philip Cohen J. Simon C. Arthur
author_sort	Meriam Nefla
title	Salt inducible kinases 2 and 3 are required for thymic T cell development
title_short	Salt inducible kinases 2 and 3 are required for thymic T cell development
title_full	Salt inducible kinases 2 and 3 are required for thymic T cell development
title_fullStr	Salt inducible kinases 2 and 3 are required for thymic T cell development
title_full_unstemmed	Salt inducible kinases 2 and 3 are required for thymic T cell development
title_sort	salt inducible kinases 2 and 3 are required for thymic t cell development
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/612ab4473bc34e1f9a8c8690879295a3
work_keys_str_mv	AT meriamnefla saltinduciblekinases2and3arerequiredforthymictcelldevelopment AT nicolajdarling saltinduciblekinases2and3arerequiredforthymictcelldevelopment AT manuelvangijselbonnello saltinduciblekinases2and3arerequiredforthymictcelldevelopment AT philipcohen saltinduciblekinases2and3arerequiredforthymictcelldevelopment AT jsimoncarthur saltinduciblekinases2and3arerequiredforthymictcelldevelopment
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Salt inducible kinases 2 and 3 are required for thymic T cell development

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