A STEP-WISE EXPANSION OF INTESTINAL INTRAEPITHELIAL T-LYMPHOCYTES IN ASSOCIATION WITH MICROBIAL COLONIZATION IS DEFINED BY SENSITIVITY TO CYCLOSPORINE-A

Murine intestinal intraepithelial lymphocytes (IELs) consist of T cell s bearing alpha beta-antigen receptor (alpha beta-IELs) and those bear ing gamma delta-antigen receptor (gamma delta-IELs). Although gamma de lta-IELs outnumber gamma delta-IELs in germ-free (GF) mice, oral inocu lation of fecal suspension from conventional (CV mice into GF mice ind uced the increase in number of alpha beta-IELs, leaving the number of gamma delta-IELs unchanged, and the number of alpha beta-IELs reached the level of CV mice by 3 weeks after coventionalization, Expansion of alpha beta-LELs and increase in their CD44(+) subset in conventionali zed mice were not affected until 2 weeks after beginning of daily inje ction of cyclosporin A (CsA). However, further expansion of alpha beta -IELs during 2-3 weeks after conventionalization was blocked by inject ion of CsA. Although the relative constitution of CD4(-) 8(-), CD4(+) 8(-), CD4(-) 8 alpha alpha(+), CD4(-) 8 alpha beta(+) and CD4(+) 8(+) subsets among alpha beta-IELs was comparable between control and CsA-t reated groups, CsA injection resulted in the decrease in ratio of high -density fraction cells to low density fraction cells in IELs. CsA com pletely abrogated the expansion of T cells in peripheral lymph nodes s timulated by alloantigens in vivo, and proliferation of IELs from GF m ice induced bq immobilized anti-alpha beta-T-cell receptor (TCR) monoc lonal antibodies (mAb) in vitro was also eliminated by CsA. These resu lts indicate that microbial colonization-induced expansion of alpha be ta-IELs is subdivided into two steps: the early phase of expansion tak es place via TCR-non-mediated pathway and the late phase of expansion requires TCR-mediated signal transduction.