Abstract
Intestinal intraepithelial lymphocytes (IELs) are distributed along the length of the intestine and are considered the frontline of immune surveillance. The precise molecular mechanisms, especially epigenetic regulation, of their development and function are poorly understood. The trimethylation of histone 3 at lysine 27 (H3K27Me3) is a kind of histone modifications and associated with gene repression. Kdm6b is an epigenetic enzyme responsible for the demethylation of H3K27Me3 and thus promotes gene expression. Here we identified Kdm6b as an important intracellular regulator of small intestinal IELs. Mice genetically deficient for Kdm6b showed greatly reduced numbers of TCRαβ+CD8αα+ IELs. In the absence of Kdm6b, TCRαβ+CD8αα+ IELs exhibited increased apoptosis, disturbed maturation and a compromised capability to lyse target cells. Both IL-15 and Kdm6b-mediated demethylation of histone 3 at lysine 27 are responsible for the maturation of TCRαβ+CD8αα+ IELs through upregulating the expression of Gzmb and Fasl. In addition, Kdm6b also regulates the expression of the gut-homing molecule CCR9 by controlling H3K27Me3 level at its promoter. However, Kdm6b is dispensable for the reactivity of thymic precursors of TCRαβ+CD8αα+ IELs (IELPs) to IL-15 and TGF-β. In conclusion, we showed that Kdm6b plays critical roles in the maturation and cytotoxic function of small intestinal TCRαβ+CD8αα+ IELs.
Highlights
Intestinal intraepithelial lymphocytes (IELs) are mainly composed of conventional CD4+ and CD8αβ+ T cells and unconventional CD8αα+ T cells [1, 2]
These results indicated that the abnormal IELs heterogeneity in Kdm6bF/FCD4Cre mice could be mainly attributed to reduced TCRαβ+ IELs and that Kdm6b played an important role in the regulation of unconventional TCRαβ+CD8αα+ IELs
Kdm6b controls the heterogeneity and T cell receptor (TCR) repertoire of small sistently, the frequency of cleaved caspase 3-positive IELPs intestinal IELs Among thymocytes (DN, DP, CD4+, and CD8+), spleen CD4+ and CD8+ T cells, thymic IELPs, and different small intestinal TCRαβ+ and TCRγδ+ IEL subsets (Fig. S1a, b), Kdm6b was expressed at showed no difference between two groups (Fig. S3e)
Summary
Intestinal intraepithelial lymphocytes (IELs) are mainly composed of conventional CD4+ and CD8αβ+ T cells and unconventional CD8αα+ T cells [1, 2]. TCRαβ+CD8αα+ IELs derive from triple-positive (TP) thymic thymocytes (CD4+CD8α+CD8β+) that seed the intestinal epithelium as CD4−CD8α−CD8β− precursor cells [4, 5]. After priming by non-self-antigens, conventional IELs upregulate the expression of α4β7, which interacts with mucosal addressin cell adhesion molecule 1 expressed by intestinal high endothelial venules, and CCR9, which can be recruited by CCL25 produced by intestinal epithelial cells (IECs). The adhesion molecule αE integrin facilitates the localization of IELs to the intestinal epithelium by interacting with E-cadherin expressed by IECs [7,8,9]. The mechanisms regulating the development of intestinal IELs remain to be further investigated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
