Altered development of intestinal intraepithelial lymphocytes in P-glycoprotein-deficient mice

Intraepithelial lymphocytes (IEL) that reside in the intestinal epithelium are known to exhibit phenotypic and functional characteristics that are dis tinct from other T cells. We have recently shown that peripheral T cells ex clusively express an isoform of P-glycoprotein (P-gp) encoded by the mdr1a gene, but do not require mdr1a expression for normal proliferative, cytokin e, or cytotoxic responses. In the present study, we have used mdr1-type kno ckout (KO) mice to demonstrate that IEL also utilize mdr1a, but only prefer entially, in that the mdr1b isoform can be expressed in the absence of mdr1 a 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 s pecific, while the total number of IEL was relatively unaffected by the abs ence of mdr1a expression, the proportions of CD8 alpha beta and TCR alpha b eta+ IEL increased significantly in mdr1a and mdr1a/b KO mice at the expens e of CD8 alpha alpha and TCR gamma delta+ IEL, respectively. Moreover. thes e subset alterations also appeared to have functional consequences, in that proliferative, IL-2. and IFN-gamma responses of IEL from KO mice were dist inct from those of normal IEL. In summary, our data suggest that mdr1a expr ession is required for the development of certain IEL subpopulations, most notably TCR gamma delta+ cells, and thereby indirectly influences the balan ce of T cell subsets in the intestinal epithelium. (C) 2000 Elsevier Scienc e Ltd. All rights reserved.