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 long-term secretion vIL-10 has a stimulatory effect on T cells. For this purpose we employed transfectants derived from a mastocytoma cell line (P815 cells, H-2(d)) constitutively secreting 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 for 7 days in the presence of P815-vIL-10 cells we could detect a marked reduction 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 after 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, paracrine 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 eliminated in DBA/2 mice, could grow if exposed to temporarily secreted vIL-10. These time-dependent immunomodulatory effects have to be considered in potential therapeutic applications of vIL-10.