Interferons (IFN) have been shown to modulate the expression of a number of cell surface antigens on macrophages and lymphocytes. Because such phenotypic alterations may be involved in the functional effects of IFN, it appears important to characterize further these alterations. In the present work, we evaluated the response to IFN of Ly-6-encoded molecules on murine T cells. Two types of Ly-6 antigens, Ly-6A and Ly-6C, normally present on minor subsets of mature T cells were studied. It was found that in vivo treatment of mice with the IFN inducer poly(I . C) or with purified IFN-alpha/beta resulted two days later in augmented expression of these antigens. Purified T cells cultured in vitro for 2 days in the presence of 5% serum from poly(I . C)-treated mice or of 10(4) units/ml IFN-alpha/beta also displayed dramatically increased (4-12-fold) amounts of Ly-6 antigens. Under the same conditions, the T cell markers Thy-1, Ly-1, Lyt-2 and MT4 were unaffected or slightly diminished while surface expression of H-2 or beta 2-microglobulin antigens was increased by only 10-36%. Therefore, poly(I . C)-induced or purified IFN interacts with resting T cells to selectively enhance Ly-6 antigen expression. This phenomenon was found to correlate functionally with increased proliferative response of the T cells, in presence of phorbol myristate acetate, to anti-Ly-6 antibodies cross-linked on their surface. Enhancement of Ly-6 antigen expression on T cells may thus play a role in IFN-mediated immunoregulation.