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

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 mdr1 a gene, but do not require mdr1 a 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 mdr1 a, but only preferentially, in that the mdr1 b 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 specific, while the total number of IEL was relatively unaffected by the absence of mdr1 a expression, the proportions of CD8αβ and TCRαβ+ IEL increased significantly in mdr1 a and mdr1 a/ b KO mice at the expense of CD8αα and TCRγδ+ IEL, respectively. Moreover, these subset alterations also appeared to have functional consequences, in that proliferative, IL-2, and IFN-γ responses of IEL from KO mice were distinct from those of normal IEL. In summary, our data suggest that mdr1 a expression is required for the development of certain IEL subpopulations, most notably TCRγδ+ cells, and thereby indirectly influences the balance of T cell subsets in the intestinal epithelium.