Age-dependent PD-1 induction restricts IL-2-driven effector T cell responses during La Crosse virus infection in mice

Abstract

Age is a major determinant of disease severity following La Crosse virus (LACV) infection, yet the immunological mechanisms underlying heightened susceptibility in children remains poorly defined. Here, we show that acute LACV infection in weanling mice induces T cell dysfunction characterized by early PD-1 upregulation and impaired effector differentiation despite evidence of activation. This state is associated with reduced IL-2-dependent STAT5 signaling, indicating a failure to respond to available cytokine cues. Although regulatory T cells expand and exhibit elevated CD25 expression, their depletion increases IL-2 levels without restoring antiviral T cell responses or viral control. In contrast, PD-1 blockade partially restores T cell activation, and combined PD-1 blockade with CD25 targeting enables robust effector differentiation and improved viral control. These findings demonstrate that checkpoint signaling limits T cell responsiveness to IL-2, uncoupling activation from differentiation and driving age-dependent susceptibility to LACV infection.