CXCL10-driven STAT3 signaling programs pathogenic CD4+ T cell responses and limits antiviral immunity during arthritogenic alphavirus infection

Abstract

Arthritogenic alphaviruses, including onyong nyong (ONNV), chikungunya virus (CHIKV), and Mayaro (MAYV) viruses, cause acute and chronic inflammatory joint disease, with disease severity and resolution influenced by host age. The immunological mechanisms governing persistent inflammation remain incompletely defined. In an age-stratified murine model we show that ONNV infection induced elevated Cxcl10 expression and viral persistence in infected tissues, accompanied by preferential accumulation of CD4+ T cells and limited recruitment of CD8+ T cells. This was associated with skewed T cell differentiation, characterized by increased STAT3 phosphorylation and ROR{gamma}t expression. Infection with CHIKV and MAYV recapitulated these features, supporting a conserved CXCL10-driven pathogenic program across arthritogenic alphaviruses. Perturbation of this axis reduced CD4+ T cell accumulation, altered T cell differentiation states, and decreased tissue viral burden. Thus, we show that a CXCL10-biased immune response is highly proinflammatory but poorly effective in mediating viral clearance, thus setting the stage for chronic disease.