Paralysis of B7 co‐stimulation through the effect of viral IL‐10 on T cells as a mechanism of local tolerance induction

The Epstein‐Barr virus (EBV) encodes an open reading frame with significant homology to the cellular IL‐10 gene. This viral IL‐10 (vIL‐10) might enable EBV to evade antiviral T cells. We employed transfectants of a murine tumor cell line (P815) to investigate whether vIL‐10 interferes with the first (antigenic) or second (co‐stimulatory) signal of T cell activation. Untransfected P815 cells caused tumors in syngeneic DBA/2 mice after s.c. inoculation. In contrast, transfectants that provided either a strong antigenic stimulus (P815‐Kb cells) or a strong co‐stimulatory signal (P815‐B7 cells) were rejected. Injection of double‐transfected P815 cells expressing Kb and secreting high levels of vIL‐10 (P815‐Kb ‐vIL‐10) did not result in tumor growth. We then investigated whether vIL‐10 could paralyse co‐stimulation by B7 under the same conditions. Therefore P815‐B7 cells were mixed with vIL‐10‐secreting P815‐Kb cells and co‐injected into DBA/2 animals. Most of these mice developed a tumor. Explanted tumor cells expressed the B7 molecule but not the Kb antigen. These observations in vivo were mirrored by experiments in vitro: vIL‐10 could induce T cell tolerance towards P815‐B7 cells but not P815‐Kb cells. Taken together our results suggest that vIL‐10 acts directly on T cells to inhibit co‐stimulatory signals mediated via B7 receptors such as CD28 or CTLA‐4.