The murine multiple drug resistance (mdr) gene, mdr1a, encodes a 170-kDa transmembrane protein that is expressed in many tissues including intestinal epithelial cells, a subset of lymphoid cells and hematopoietic cells. We report that mdr1a knockout (mdr1a−/−) mice are susceptible to developing a severe, spontaneous intestinal inflammation when maintained under specific pathogen-free animal facility conditions. The intestinal inflammation seen in mdr1a−/− mice has a pathology similar to that of human inflammatory bowel disease (IBD) and is defined by dysregulated epithelial cell growth and leukocytic infiltration into the lamina propria of the large intestine. Treating mdr1a−/− mice with oral antibiotics can both prevent the development of disease and resolve active inflammation. Lymphoid cells isolated from mice with active colitis are functionally reactive to intestinal bacterial Ags, providing evidence that there is enhanced immunologic responsiveness to the normal bacterial flora during IBD. This study is the first description of spontaneous colitis in a gene knockout mouse with an apparently intact immune system. This novel model of spontaneous colitis may provide new insight into the pathogenesis of IBD, the nature of dysregulated immune reactivity to intestinal bacterial Ags, and the potential functional role of mdr genes expressed in the cells and tissues of the colonic microenvironment.

We examined the appearance of intestinal intraepithelial lymphocytes (IEL) during the first 12 wk of life to gain insight into postnatal factors that contribute to the differences found between IEL in the large and small intestines of adult mice. Intestinal T cells were very infrequent at birth, but increased in number in the large and small intestine during the first 4 wk of life and then stabilized. The small intestinal epithelium at 2 wk of age contained mostly T cell receptor (TCR) ␣␤ϩ, CD2ϩ T cells, unlike IEL in adult mice, which were composed of nearly equal proportions of CD2Ϫ, TCR ␣␤ϩ and TCR ␥␦ϩ cells. Between 2 and 3 wk of age, TCR ␥␦ϩ, CD2Ϫ IEL increased greatly in the small intestine, whereas TCR ␣␤ϩ cells expressing CD2 decreased. By contrast, IEL in the large intestine at 2 and 3 wk of age were mostly TCR ␣␤ϩ, CD2ϩ T cells similar to large intestinal IEL in adult mice. And finally, the expression of CD69 increased earlier and to higher levels on TCR ␣␤ϩ and TCR ␥␦ϩ IEL in the small intestine than in the large intestine. Our results demonstrate that IEL in the large and small intestine are phenotypically similar during suckling and that differences between these populations are established after weaning. Furthermore, the earlier accumulation of IEL with an activated adult IEL phenotype in the small intestine suggests that these T cells mature or expand in the gut and contribute to the maturation of immune function during postnatal life in mice. The mucosal immune system of the intestine consists of lymphocytes located in anatomically distinct, but functionally related regions comprising the largest immune effector site in the body. Lymphocytes located within the intestinal epithelium are almost exclusively T cells, called IEL (1). SI-IEL are mostly CD8ϩ, CD4Ϫ T cells (60 -70%), which express a TCR composed of ␥ and ␦ chains (TCR ␥␦; 40 -50%) or ␣ and ␤ chains (TCR ␣␤; 50 -60%) (1-3). This is unlike T cells found in peripheral blood and nonmucosal lymphoid organs, which are mostly TCR ␣␤ϩ cells that express either CD4 or CD8 in nearly equal proportions. Furthermore, most SI-IEL in mice express a unique form of CD8, the CD8␣␣ homodimer, whereas the majority of CD8ϩ T cells in the lymph node and spleen express the CD8␣␤ heterodimer (1, 4, 5). Other T cell surface proteins distinguish IEL from peripheral T cells. The majority of IEL isolated de novo express the activation antigen, CD69, and a unique mucosal integrin, ␣ E␤7 , whereas the majority of resting T cells in the periphery lack these proteins (6 -8). Furthermore, most SI-IEL do not express the lymph node homing receptor, CD62L, or the costimulatory ligand, CD2, proteins that are expressed by a majority of T cells found in lymph node and spleen (6,7,9). Taken together, these data demonstrate that IEL are distinct from T cells found in nonmucosal sites.Intestinal mucosal T cells share some common features, although there are important regional differences between IEL in the small and large intestine and between IEL and T cells found in the lamina...

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Intraepithelial lymphocytes (IEL) are found in both the small and the large intestine. We demonstrate that there are a number of striking phenotypic and functional differences between the two populations of IEL isolated from mice. In the large intestine, the majority of IEL express the alpha beta TCR, and among these TCR-alpha beta+ lymphocytes, CD4+ cells are as prevalent as CD8+ cells. In contrast, in the small intestine, most of the TCR-alpha beta+ IEL express CD8, and an increased percentage of cells express TCR-gamma delta. In addition, most TCR-gamma delta+ IEL isolated from the large intestine (LI-IEL) are CD4- CD8- cells, as compared to TCR-gamma delta+ IEL isolated from the small intestine (SI-IEL), which are predominantly CD8+. Furthermore, CD2 and the lymph node homing receptor, L-selectin, are expressed by most LI-IEL but not by SI-IEL. Furthermore, LI-IEL have much less cytolytic activity than SI-IEL. These data suggest that LI-IEL are a distinct population of lymphocytes that may have a different immunologic role than that of SI-IEL.