Division of Cell Signalling and Immunology, Wellcome Trust Building, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
MRC Protein Phosphorylation and Ubiquitylation Unit, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Sci Rep. 2021 Nov 3;11(1):21550. doi: 10.1038/s41598-021-00986-0.
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.
盐诱导激酶（SIK）有 3 种同工型，已被确定在先天免疫、代谢控制和神经元功能中发挥作用，但它们在适应性免疫中的作用尚不清楚。为了解决这一差距，我们使用了 SIK 敲除和激酶失活敲入小鼠的组合。SIK1 和 SIK2 活性的联合缺失并未阻止 T 细胞的发育。在造血细胞中，由 Vav-iCre 转染体驱动的 SIK3 条件性敲除导致外周 T 细胞数量适度减少，但 B 细胞数量正常。造血细胞中 SIK2 的组成性敲除与 SIK3 的条件性敲除相结合，导致外周 T 细胞数量严重减少，而不减少 B 细胞数量。当 SIK3 缺失通过 CD4-Cre 转染体驱动以在 T 细胞发育的 DP 阶段缺失时，也观察到类似的效果。对 SIK2/3 Vav-iCre 小鼠的分析表明，胸腺细胞数量大大减少，但发育并未完全受阻，因为存在数量较少的 CD4 和 CD8 单阳性细胞。SIK2 和 SIK3 不参与 TCRβ基因座的重排，也不参与 CD4/CD8 双阳性胸腺细胞表面 TCR 复合物的低水平细胞表面表达。在缺乏 SIK2 和 SIK3 的情况下，向成熟单阳性细胞的进展大大减少，表明在胸腺中存在阴性和/或阳性选择缺陷。与阴性选择的影响一致，在 SIK2/3 敲除小鼠的胸腺 TCRbeta 高/CD5 阳性细胞中观察到凋亡增加。总之，这些结果表明 SIK2 和 SIK3 在胸腺 T 细胞发育中具有重要作用。
