Graduate fellow Rutgers Robert Wood Johnson Med. Sch. New Brunswick, New Jersey, United States
Introduction/Rationale: La Crosse virus (LACV) is the leading cause of pediatric arboviral encephalitis in the United States, with severe disease predominating in children and weanling mice. The immunological basis for this age-dependent susceptibility remains poorly defined. We previously established that adult mice mount robust LACV-specific CD4⁺ and CD8⁺ T cell responses that mediate viral clearance, whereas weanlings fail to generate protective effector responses. Here, we identify programmed cell death protein 1 (PD-1) signaling as a central driver of T cell dysfunction in weanlings.
Methods: Weanling and adult C57BL/6 mice were infected with LACV, and immune responses were analyzed by flow cytometry. PD1 blockade was performed in vivo to assess effects on T cell activation and antiviral functions.
Results: Flow cytometric profiling revealed marked upregulation of PD-1 on both CD4⁺ and CD8⁺ T cells following infection, accompanied by elevated PD-L1 expression in infected brain tissue, consistent with an inhibitory microenvironment. Functionally, PD-1^hi T cells in weanlings exhibited reduced CD44 upregulation, impaired IFN-γ production, and diminished cytolytic potential compared to adult counterparts. In vivo PD-1 blockade restored CD8⁺ T cell activation, enhanced granzyme B and IFN-γ expression, and increased the frequency of virus-specific effector cells as early as six days post-infection. Ongoing studies are assessing whether enhanced T cell activation following PD-1 blockade translates to improved viral control.
Conclusion: Together, these findings define PD-1-mediated T cell suppression as a mechanistic correlate of age-dependent susceptibility to LACV and suggest that early checkpoint blockade may restore antiviral immunity in immature hosts.
