MicroRNA-150 controls differentiation of intraepithelial lymphocytes through TGF-? receptor II regulation - 05/04/18

Doi : 10.1016/j.jaci.2017.07.019

Sang-Hwan Seo, PhD ^a,^{∗
These authors contributed equally to this work.}, Min Seong Jang, DVM, PhD ^b,^{∗
These authors contributed equally to this work.}, Doo-Jin Kim, PhD ^b,^{∗
These authors contributed equally to this work.}, 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,^⁎,^{‡
These authors contributed equally to this work.} , Tae-Don Kim, PhD ^a,^c,^⁎,^{‡
These authors contributed equally to this work.}
^a Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
^b Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
^d the Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
^c Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
^e Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Korea
^f Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea

^∗Corresponding author: Inpyo Choi, PhD, or Tae-Don Kim, PhD, KRIBB, Immunotherapy Research Center, 125 Gwahakro Yuseong-gu, Daejeon, 34141 Korea.KRIBBImmunotherapy Research Center125 Gwahakro Yuseong-gu, Daejeon34141Korea

Abstract

Background

Intraepithelial lymphocytes (IELs) in the intestines play pivotal roles in maintaining the integrity of the mucosa, regulating immune cells, and protecting against pathogenic invasion. Although several extrinsic factors, such as TGF-β, have been identified to contribute to IEL generation, intrinsic regulatory factors have not been determined fully.

Objective

Here we investigated the regulation of IEL differentiation and the underlying mechanisms in mice.

Methods

We analyzed IELs and the expression of molecules associated with IEL differentiation in wild-type control and microRNA (miRNA)-150 knockout mice. Methotrexate was administered to mice lacking miR-150 and control mice.

Results

miR-150 deficiency reduced the IEL population in the small intestine and increased susceptibility to methotrexate-induced mucositis. Evaluation of expression of IEL differentiation–associated molecules showed that miR-150–deficient IELs exhibited decreased expression of TGF-β receptor (TGF-βR) II, CD103, CD8αα, and Runt-related transcription factor 3 in all the IEL subpopulations. The reduced expression of TGF-βRII in miR-150–deficient IELs was caused by increased expression of c-Myb/miR-20a. Restoration of miR-150 or inhibition of miR-20a recovered the TGF-βRII expression.

Conclusion

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.

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Graphical abstract

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Key words : MicroRNA, intraepithelial lymphocytes, TGF-β, CD103, Runt-related transcription factor 3, intestinal epithelium, mucositis, methotrexate

Abbreviations used : AANAT, DC, DN, IEL, IL-15R, KRIBB, LP, MED12, miR, mLN, MTX, Myb, NK, RA, Runx3, TCR, TGF-βR, TLA, UTR, WT

Plan

Methods

Mice

Bone marrow transfer model

Experimental mucositis model

In vitro IEL differentiation

Statistics

Results

miR-150 deficiency limits IELs in the small intestine

Reduced IEL populations in mir-150^−/− mice are not associated with miR-150 deficiency in intestinal epithelial cells

miR-150 does not affect the number or function of IEL-generating CD103⁺ dendritic cells

Generation of IEL precursors is miR-150 independent

TGF-βRII expression is reduced in miR-150–deficient IELs

miR-150 deficiency downregulates TGF-βRII expression by suppressing the c-Myb/miR-20a pathway

miR-150 restoration or miR-20a inhibition recovers TGF-βRII and CD103 expression levels in mir-150^−/− IELs

Discussion

	Supported by the KRIBB Research Initiative Program, a National Research Foundation of Korea (NRF) grant (NRF-2016R1A2B4014230), and a National Research Council of Science & Technology (NST) grant (CRC-15-02-KRIBB) from the Korean government (MSIP).
	Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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MicroRNA-150 controls differentiation of intraepithelial lymphocytes through TGF-? receptor II regulation - 05/04/18

Abstract

Background

Objective

Methods

Results

Conclusion

Graphical abstract

Plan

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