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Originally published In Press as doi:10.1074/jbc.M205300200 on July 22, 2002

J. Biol. Chem., Vol. 277, Issue 40, 37811-37819, October 4, 2002
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A Gnotobiotic Transgenic Mouse Model for Studying Interactions between Small Intestinal Enterocytes and Intraepithelial Lymphocytes*,

Indira U. MysorekarDagger , Robin G. Lorenz§, and Jeffrey I. GordonDagger ||

From the Departments of Dagger  Molecular Biology and Pharmacology and § Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110

The mouse intestinal epithelium undergoes continuous renewal throughout life. Intraepithelial lymphocytes (IELs) represent a significant fraction of this epithelium and play an important role in intestinal mucosal barrier function. We have generated a germ-free transgenic mouse model to examine the effects of a genetically engineered proliferative abnormality in the principal epithelial cell lineage (enterocytes) on IEL census and on IEL-enterocytic cross-talk. SV40 large T antigen (TAgWt) or a mutant derivative (TAgK107/8) that does not bind pRB was expressed in small intestinal villus enterocytes under the control of elements from the intestinal fatty acid binding protein gene (Fabpi). Quantitative immunohistochemical and flow cytometric analyses of conventionally raised and germ-free FVB/N Fabpi-TAgWt, Fabpi-TAgK107/8, and nontransgenic mice disclosed that forced reentry of enterocytes into the cell cycle is accompanied by an influx of thymically educated alpha beta T cell receptor (TCR)+ CD4+ and alpha beta TCR+ CD8alpha beta + IELs and a decrease in intestinally derived gamma delta TCR+ CD8alpha alpha IELs. Real time quantitative reverse transcriptase-PCR studies of jejunal villus epithelium recovered from germ-free transgenic and normal mice by laser capture microdissection and gamma delta TCR+ jejunal IELs purified by flow cytometry disclosed that the proliferative abnormality is accompanied by decreased expression of enterocytic interleukin-7 as well as IEL interleukin-7Ralpha and transforming growth factor beta 3. The analysis also revealed that normal villus epithelium expresses Fms-like tyrosine kinase 3 (Flt3), a known regulator of hematopoietic stem cell proliferation and neuronal cell survival, and its ligand (Flt3L). Epithelial expression of this receptor and its ligand is reduced by the proliferative abnormality, whereas IEL expression of Flt3L remains constant. Together, these findings demonstrate that changes in the proliferative status of the intestinal epithelium affects maturation of gamma delta TCR+ IELs and produces an influx of alpha beta TCR+ IELs even in the absence of a microflora.

* This work was supported in part by National Institutes of Health Grant DK30292.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains one table.

Present address: Dept. of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233.

|| To whom correspondence should be addressed: Dept. of Molecular Biology and Pharmacology, Box 8103, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-7243; Fax: 314-362-7047; E-mail: jgordon@molecool.wustl.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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