Dehydroepiandrosterone (DHEA) is an adrenal steroid hormone produced in abundance by humans and most other warm-blooded animals, is uniquely sulfated (DHEAS) prior to export into the plasma, and exhibits an age-related decline in production with progressive age. No major physiological functions have been ascribed to the activity of this steroid, although DHEA is known to serve as an intermediary in sex steroid synthesis. Studies on the effects of glucocorticoids (GCS) on the immune system led us to question whether DHEA had effects on the ability of activated lymphocytes to produce interleukin 2 (IL 2). We determined that (a) lymphocytes from DHEA- or DHEAS-treated mice consistently produced much greater levels of IL 2 than normals in response to stimulation, (b) direct lymphocyte exposure to DHEA at low doses (10(-10)-10(-7) M) caused an enhanced capacity to secrete IL 2 following activation, (c) IL 2 production by activated cloned T cell lines could be augmented by DHEA treatment, and (d) GCS-induced depressions in IL 2 synthesis by T cells or T cell clones could be overcome in vitro and in vivo by exposure to the effects of DHEA. These findings suggest that DHEA, presumably through receptor-mediated mechanisms similar to other types of steroid hormones, may represent a natural and important regulator of IL 2 production in both normal and pathologic conditions.