Altered development of intestinal intraepithelial lymphocytes in P-glycoprotein-de®cient mice Michael D. Eisenbraun a , R. Lee Mosley b, 1 , Daniel H. Teitelbaum c , Richard A. Miller a,b,d, * a Cellular and Molecular Biology Graduate Program, University of Michigan School of Medicine, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0940, USA b Department of Pathology, University of Michigan School of Medicine, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0940, USA c Section of Pediatric Surgery, Department of Surgery, C.S. Mott's Children's Hospital, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0940, USA d Geriatrics Center, Institute of Gerontology, V.A. Medical Center, 5316 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0940, USA Received 6 December 1999; received in revised form 27 March 2000; accepted 3 April 2000 Abstract Intraepithelial lymphocytes (IEL) that reside in the intestinal epithelium are known to exhibit phenotypic and functional characteristics that are distinct from other T cells. We have recently shown that peripheral T cells exclusively express an isoform of P-glycoprotein (P-gp) encoded by the mdr1a gene, but do not require mdr1a expression for normal proliferative, cytokine, or cytotoxic responses. In the present study, we have used mdr1-type knockout (KO) mice to demonstrate that IEL also utilize mdr1a, but only preferentially, in that the mdr1b isoform can be expressed in the absence of mdr1a expression. We also report that a high level of P-gp activity appears to be necessary for the normal development of certain IEL subpopulations. In speci®c, while the total number of IEL was relatively unaected by the absence of mdr1a expression, the proportions of CD8ab and TCRab+ IEL increased signi®cantly in mdr1a and mdr1a/b KO mice at the expense of CD8aa and TCRgd+ IEL, respectively. Moreover, these subset alterations also appeared to have functional consequences, in that proliferative, IL-2, and IFN-g responses of IEL from KO mice were distinct from those of normal IEL. In summary, our data suggest that mdr1a expression is required for the development of certain IEL subpopulations, most notably TCRgd+ cells, and thereby indirectly in¯uences the balance of T cell subsets in the intestinal epithelium. 7 2000 Elsevier Science Ltd. All rights reserved. Developmental and Comparative Immunology 24 (2000) 783±795 0145-305X/00/$ - see front matter 7 2000 Elsevier Science Ltd. All rights reserved. PII: S0145-305X(00)00029-X www.elsevier.com/locate/devcompimm 1 Present address: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA. * Corresponding author. Tel.: +1-734-936-2122; fax: +1-734-936-9220. E-mail address: millerr@umich.edu (R.A. Miller). Abbreviations: IEL, intraepithelial lymphocytes; KO, knockout; LN, lymph node; P-gp, P-glycoprotein; R-123, rhodamine-123; TCR, T cell receptor; wt, wild-type.