TRANSFORMING GROWTH FACTOR-BETA(2) INDUCES APOPTOSIS OF MURINE T-CELLCLONES WITHOUT DOWN-REGULATING BCL-2 MESSENGER-RNA EXPRESSION

Transforming growth factor-beta (TGF beta) is a potent immunosuppressi ve cytokine which inhibits the antigen (Ag)-dependent expansion of T c ells both in vitro and in vivo by mechanisms not well defined yet. Her e we report that exposure of interleukin (IL)-2-dependent T cell lines to TGF beta(2) results in apoptosis defined by morphology, nucleosoma l size DNA fragmentation and in situ DNA end labeling. TGF beta(2)-ind uced T cell apoptosis showed the following characteristics: (1) in con trast to the rapid evolution of apoptosis following IL-2 deprivation, apoptosis of T cells triggered by TGF beta 2 was delayed; (2) cyclohex imide prevented TGF beta(2)-induced apoptosis of CTLL-2 but not of OVA -7 T helper cells; (3) in contrast to apoptosis following IL-2 depriva tion. TGF beta(2)-mediated T cell apoptosis was not associated with de creased expression of the proto-oncogenes, bcl-2 or c-myc; (4) TGF bet a(2)-induced apoptosis was not restricted to IL-2-dependent T cell lin es since the IL-4-dependent T cell line, CT.4S, as well as EL4 lymphom a cells, which grow independently of exogenous IL-2, were also suscept ible to TGF beta(2)-mediated apoptosis. Taken together, these data may present a novel mechanism of TGF beta(2)-mediated suppression of T ce ll expansion in response to Ag and IL-2, the activation of the endogen ous death program of apoptosis, which appears to operate independently of direct interactions of TGF beta(2) with the IL-2/IL-2 receptor sys tem.