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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.

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

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