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Trans-Presentation of IL-15 by Intestinal Epithelial Cells Drives Development of CD8 IELs¹

Department of Immunology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030

IL-15 is crucial for the development of intestinal intraepithelial lymphocytes (IEL) and delivery is mediated by a unique mechanism known as trans-presentation. Parenchymal cells have a major role in the trans-presentation of IL-15 to IELs, but the specific identity of this cell type is unknown. To investigate whether the intestinal epithelial cells (IEC) are the parenchymal cell type involved, a mouse model that expresses IL-15R exclusively by the IECs (Villin/IL-15R Tg) was generated. Exclusive expression of IL-15R by the IECs restored all the deficiencies in the CD8⁺TCRβ⁺and CD8⁺TCR⁺ subsets that exist in the absence of IL-15R. Interestingly, most of the IEL recovery was due to the preferential increase in Thy1^low IELs, which compose a majority of the IEL population. The differentiation of Thy1^highCD4^–CD8^– thymocytes into Thy1^–CD8 IELs was found to require IL-15R expression specifically by IECs and thus, provides evidence that differentiation of Thy1^low IELs is one function of trans-presentation of IL-15 in the intestines. In addition to effects in IEL differentiation, trans-presentation of IL-15 by IECs also resulted in an increase in IEL numbers that was accompanied by increases in Bcl-2, but not proliferation. Collectively, this study demonstrates that trans-presentation of IL-15 by IECs alone is completely sufficient to direct the IL-15-mediated development of CD8⁺ T cell populations within the IEL compartment, which now includes a newly identified role of IL-15 in the differentiation of Thy1^low IELs.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Research is supported by National Institutes of Health Grant AI070910 and the M.D. Anderson Trust Fellowship (to K.S.).

L.J.M. performed a majority of the experiments, analyzed, interpreted data, and cowrote the manuscript. L.A. performed Western blots; T.L. analyzed confocal images; and K.S.S. designed, analyzed, interpreted data, and cowrote the manuscript.

² Address correspondence and reprint requests to Dr. Kimberly S. Schluns, Department of Immunology, M/C 901, UT MDACC, P.O. Box 301429, Houston, TX 77030. E-mail address: kschluns{at}mdanderson.org

³ Abbreviations used in this paper: IEL, intraepithelial lymphocyte; IEC, intestinal epithelial cell; Wt, wild type; TG, transgenic; IRES, internal ribosome entry site; EGFP, enhanced GFP.

⁴ The online version of this article contains supplemental material.