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

Abstract

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‐2d) 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 × 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.