Distinct and synergistic immunomodulatory roles of PSGL-1 and PD-1 in CP versus NCP BVDV-1 infections: A novel mechanism of CD8 T-cell exhaustion and viral pathogenesis.

Bovine viral diarrhea virus-1 (BVDV-1), recently reclassified as Pestivirus bovis, exists in cytopathic (CP) and non-cytopathic (NCP) biotypes and causes significant economic losses due to immunosuppression. However, the roles of specific immune checkpoints in BVDV pathogenesis remain unclear. This study investigated the immunomodulatory functions of programmed death-1 (PD-1) and P-selectin glycoprotein ligand-1 (PSGL-1) in murine models of CP and NCP BVDV infection. Both biotypes upregulated PD-1 and PSGL-1 expression on peripheral blood lymphocytes and CD8⁺ T cells, leading to leukopenia, lymphopenia, impaired proliferation, reduced IFN-γ secretion, increased apoptosis, and pathological damage. In CP BVDV infection, blockade of PD-1 or PSGL-1, alone or in combination, elevated leukocyte counts, enhanced CD8 T-cell activation and proliferation, reduced pathology, inhibited viral replication, and activated the PI3K/Akt/mTOR pathway. In NCP BVDV infection, PSGL-1 blockade alone was ineffective, and significant immune improvement was achieved only through combined PD-1/PSGL-1 blockade, indicating a PD-1-dependent role for PSGL-1 in NCP BVDV infection. Mechanistically, PSGL-1 exhibits immune checkpoint-like activity in CP BVDV infection but acted as a co-regulator dependent on PD-1 signaling in NCP infection. These findings reveal a novel, biotype-specific mechanism of immune checkpoint regulation and provide a theoretical basis for biotype-tailored immunomodulatory strategies against BVDV infection in cattle.