We have studied the direct effect of retinoic acid on the antigen-specific proliferative response of a T lymphocyte clone and have investigated the related expression of the retinoic acid receptor-alpha gene (RAR-alpha). Retinoic acid provided direct growth support, in a dose-dependent manner, for hen egg white lysozyme (HEL)-activated T lymphocytes in serum-free medium. The increase of T lymphocyte proliferation supported by retinoic acid was dose dependent, and best effects were achieved at physiological concentrations (10(-9)-10(-7) mol/liter). Expression of RAR-alpha mRNA in antigen-stimulated T lymphocyte cultures was upregulated by retinoic acid in a dose-dependent manner; maximal expression occurred within 6 hr of culture and in response to 10(-9)-10(-7) mol/liter retinoic acid. Lower expression of RAR-alpha was attained by antigen or mitogen (concanavalin A) in the absence of externally added retinoic acid. The inclusion of retinoic acid at the time of HEL processing led to increased T lymphocyte proliferation, provided antigen presenting cell cultures had been maintained for 16 hr. Our results indicate that retinoic acid and RAR-alpha might function in T lymphocytes in a manner similar to that described in other cell systems, namely as ligand-inducible transcriptional enhancer factors.