IL-27 suppresses CD4 and CD8 T cell cytotoxicity and viral control during cytomegalovirus infection

Abstract Cytomegalovirus (CMV) is a large DNA β-herpes virus that infects the majority of humans and is endemic in wild mice. CMV establishes life-long latency with sporadic reactivation, and both primary infection and reactivation can cause serious disease in patients with compromised or naïve immunity. Horizontal CMV transmission commonly occurs through prolonged replication in the salivary gland (SG). In mice, CD4 T cells are absolutely required to curtail SG persistence, whereas CD8 T cells control acute systemic infection. Both CD4 and CD8 CMV-specific T cells from infected individuals display a strong cytotoxic phenotype and are able to kill target cells ex vivo. However, the immune factors that promote or regulate differentiation of these cytotoxic T cells remain largely unclear. Here we show that the pleiotropic cytokine IL-27 plays a key role in regulating CMV-specific T cell responses. Infection of mice deficient for the IL-27 receptor a subunit (Il27ra −/−) with mouse CMV (MCMV), resulted in enhanced expression of KLRG1 by both CD4 and CD8 T cells, a marker associated with terminal differentiation and cytotoxicity. Consistently, MCMV-specific CD4 and CD8 T cells from Il27ra −/− mice showed increased expression of both granzyme A and FasL. Importantly, this enhanced cytotoxic phenotype correlated with improved control of MCMV persistence in the SG. Taken together, our data reveal an unexpected and novel role for IL-27 in restricting T cell cytotoxicity and control of MCMV persistence, and suggest that targeting IL-27 has the potential to limit disease caused by persistent viral infection.