CXCL10 chemokine regulates heterogeneity of the CD8+ T cell response and viral set point during chronic infection

Abstract

CD8⁺ T cells responding to chronic infection adapt an altered differentiation program that provides some restraint on pathogen replication yet limits immunopathology. This adaptation is imprinted in stem-like cells and propagated to their progeny. Understanding the molecular control of CD8⁺ T cell differentiation in chronic infection has important therapeutic implications. Here, we find that the chemokine receptor CXCR3 is highly expressed on viral-specific stem-like CD8⁺ T cells and that one of its ligands, CXCL10, regulates the persistence and heterogeneity of responding CD8⁺ T cells in spleens of mice chronically infected with lymphocytic choriomeningitis virus. CXCL10 is produced by inflammatory monocytes and fibroblasts of the splenic red pulp, where it grants stem-like cells access to signals promoting differentiation and limits their exposure to pro-survival niches in the white pulp. Consequently, functional CD8⁺ T cell responses are greater in Cxcl10^-/- mice and are associated with a lower viral set point.

Keywords: CD8+ T cells; CXCL10; CXCR3; LCMV; T cell exhaustion; TCF-1; T cell differentiation; chemokine; chronic viral infection.