Sang-Hwan Seo, PhD,a* Min Seong Jang, DVM, PhD, b* Doo-Jin Kim, PhD, b* Seok-Min Kim, BS,a,c Se-Chan Oh, MS,a,c Cho-Rok Jung, PhD,d Yunji Park, PhD,e Sang-Jun Ha, PhD,f, Haiyoung Jung, PhD,a,c Young-Jun Park, PhD,a,c Suk Ran Yoon, PhD,a,c Inpyo Choi, PhD a,c ‡,*, & Tae-Don Kim, PhDa,c, ‡,*
a Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Korea.
b Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Korea.
c Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, 34141, Korea.
d Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Korea.
e Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, 37673, Korea.
f Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Korea.
*These authors contributed equally to this work.
‡ These authors contributed equally to this work.
Correspondence and requests for materials should be addressed to I.C. or T.D.K.
Intraepithelial lymphocytes (IELs) in the intestines play pivotal roles in maintaining the integrity of the mucosa, regulating the immune cells, and protecting against pathogenic invasion. Although several extrinsic factors such as transforming growth factor-β (TGF-β) have been identified to contribute to IEL generation, intrinsic regulatory factors have not been fully determined.
Here, we investigated the regulation of IEL differentiation and the underlying mechanisms in mice.
We analyzed IELs and the expression of molecules associated with IEL differentiation in wildtype control and microRNA-150-knockout mice. Methotrexate (MTX) was administered to mice lacking microRNA (miR)-150 and control mice.
miR-150 deficiency reduced the IEL population in the small intestine and increased susceptibility to MTX-induced mucositis. Evaluation of expression of IEL differentiation-associated molecules showed that miR-150-deficient IELs exhibited decreased expression of TGF-β receptor II (TGF-βRII), CD103, CD8αα, and RUNX3 in all the IEL subpopulations. The reduced expression of TGF-βRII in miR-150-deficient IELs was caused by the increased expression of c-Myb/miR-20a. Restoration of miR-150 or inhibition of miR-20a recovered the TGF-βRII expression.
miR-150 is an intrinsic regulator of IEL differentiation through TGF-βRII regulation. miR-150-mediated IEL generation is crucial for maintaining intestinal integrity against anticancer drug-induced mucositis.
Keywords : MicroRNA; Intraepithelial lymphocytes; TGF-β; CD103; RUNX3; Intestinal epithelium; Mucositis; Methotrexate