INCREASED LFA-1-MEDIATED HOMOTYPIC CELL-ADHESION IS ASSOCIATED WITH THE G(1) GROWTH ARREST INDUCED BY RAPAMYCIN IN A T-CELL LYMPHOMA

The immunosuppressive macrolide, rapamycin, impedes the G(1) to S cell cycle progression in cytokine-stimulated normal lymphocytes and in ce rtain autonomously proliferating cell lines. Here, we found that the r apamycin-induced growth arrest augments homotypic aggregation in the Y AC-1 T cell lymphoma. The growth arrest and increased aggregation were both blocked by the rapamycin antagonist, L-685,818, which interacts with the intracellular binding proteins mediating rapamycin's biochemi cal action. Moreover, rapamycin-induced aggregation was not seen in YA C-1 cell mutants selected for resistance to the drug's antiproliferati ve effect. Although the inhibition of G(1)/S progression induced by se rum deprivation also resulted in increased cellular aggregation, cell cycle blockade in late G(1) by mimosine, early S phase by hydroxyurea, or G(2)/M by nocodazole all failed to do so. Furthermore, the aggrega tion induced by rapamycin was blocked by antibodies to the alpha (CD11 a) or beta (CD18) subunits of the integrin, LFA-1, or to its ligands, ICAM-1 and ICAM-2, and did not occur in LFA-l-deficient YAC mutants. H owever, the surface expression of LFA-1, ICAM-1, or ICAM-2 was not aug mented in cells aggregated by rapamycin. Finally, the serine/threonine protein phosphatase inhibitor, okadaic acid, was found to abrogate ra pamycin-induced aggregation. Therefore, rapamycin's impairment of YAC- I cell growth in G(1) is accompanied by enhanced LFA-1-mediated homoty pic cell adhesion that may reflect an increase of the integrin's avidi ty for its ligands and may involve protein phosphorylation/dephosphory lation events. This suggests the existence of a link between cell cycl e progression and ''inside-out'' LFA-1 signaling, possibly regulated b y rapamycin's biochemical targets. (C) 1995 Academic Press, Inc.