Loss of SOCS1 in dendritic cells increases dendritic cell maturation and decreases the CD8 T cell response to Listeria monocytogenes.

Abstract

Abstract The suppressor of cytokine signaling (SOCS) family is a group of structurally related proteins characterized by a central SH2 domain that targets the SOCS proteins to specific molecules within the JAK-STAT pathway, and a SOCS-box domain that promotes degradation of the cytokine-receptor complex. SOCS-1 is induced by cellular activation and serves as a negative feedback mechanism for a range of cytokines. It has been described that silencing SOCS-1 in dendritic cells (DC) enhances antigen presentation, T cell priming, and anti-tumor immunity. Therefore, inhibition of SOCS-1 could profoundly augment the potency of the L. monocytogenes (Lm) based cancer vaccines that we are testing in clinical studies. We questioned the role of SOCS-1 in dendritic cells in vivo during intracellular infection, a scenario where antigen-specific T cells are required for microbial clearance. To test this we characterized the infection and immune response to Lm in CD11c-Cre × SOCS1fl/fl mice that have a SOCS1 deficiency in DC. DC lacking SOCS1 showed increased maturation in vivo at baseline, but showed equivalent responses to vaccination with DC-targeted antigens combined with α-CD40. We found that Lm can be recovered from spleens and livers from mice with SOCS1-deficient DC at similar levels to that of the wild type animals. However, mice with SOCS1-deficient DC showed a dramatic defect in the specific-CD8+ T cell response while the specific-CD4+ T cells response was not affected. The lack of CD8+ T cells response correlated with low levels of IFN-γ and MCP-1 in serum during the first days of infection and decreased NK maturation. Our results demonstrate that SOCS1 expression in DC is critical to generate a strong CD8 T cell response to Lm.