T cell stimulation upon long-term secretion of viral IL-10

Viral IL-10 (vIL-10), the IL-10 homologue of Epstein-Barr virus, has so far been described as a cytokine that solely inhibits T cell function. Here we show in vivo and in vitro that after longterm secretion vIL-10 has a stimu latory effect on T cells. For this purpose we employed transfectants derive d from a mastocytoma cell line (P815 cells, H-2(d)) constitutively secretin g vIL-10 (P815-vIL-10) or expressing the co-stimulatory molecule B7-1 (P815 -B7). After in vitro stimulation of splenocytes from syngeneic DBA/2 mice f or 7 days in the presence of P815-vIL-10 cells we could detect a marked red uction of proliferation as well as cytotoxicity against P815 target cells. However, this inhibitory effect was reversed when stimulation with P815-vIL -10 cells was extended to 14 days. In vivo P815-vIL-10 cells were rejected whereas P815 cells transfected with a control plasmic were tumorigenic afte r injection into syngeneic DBA/2 mice. Furthermore, this stimulatory effect of constitutive vIL-10 secretion could be exploited to irradicate already established P815 tumors which were smaller than 5 x 5 mm. In contrast, para crine vIL-10 secretion for a limited time period of 8-9 days was associated with inhibitory effects in vivo: P815-B7 cells, which are normally elimina ted in DBA/2 mice, could grow if exposed to temporarily secreted vIL-10 . T hese time-dependent immunomodulatory effects have to be considered in poten tial therapeutic applications of vIL-10.