PD-1-Mediated PI3K/Akt/mTOR, Caspase 9/Caspase 3 and ERK Pathways Are Involved in Regulating the Apoptosis and Proliferation of CD4 and CD8 T Cells During BVDV Infection .

Acute infection of bovine viral diarrhea virus (BVDV) is associated with immune dysfunction and can cause peripheral blood lymphopenia and lymphocyte apoptosis. Our previous study has confirmed that programmed death-1 (PD-1) blockade inhibits peripheral blood lymphocyte (PBL) apoptosis and restores proliferation and anti-viral immune functions of lymphocytes after BVDV infection . However, the immunomodulatory effects of PD-1 pathway on major PBL subsets are unclear and their underlying molecular mechanisms need to be further studied. Therefore, in this study, we examined PD-1 expression in bovine PBL subsets after BVDV infection and analyzed the effects of PD-1 blockade on the apoptosis and proliferation of CD4 and CD8 T cells and expression of PD-1 downstream signaling molecules. The results showed that PD-1 expression was enhanced on CD4 and CD8 T cells, but not on CD21 B cells after cytopathic (CP) BVDV (strain NADL) and non-cytopathic (NCP) BVDV (strain KD) infection and PD-1 blockade significantly reduced the apoptosis of CD4 and CD8 T cells after these two strains infection. Remarkably, PD-1 blockade significantly increased the proliferation of CD4 and CD8 T cells after CP BVDV infection, but only significantly increased the proliferation of CD4 T cells after NCP BVDV infection. In addition, we confirmed that PD-1-mediated PI3K/Akt/mTOR, caspase 9/caspase 3 and ERK pathways are involved in regulating the apoptosis and proliferation of CD4 and CD8 T cells during BVDV infection . Notably, ERK is involved in the regulation mechanism PD-1 mediated only when the cells are infected with CP BVDV. Our findings provide a scientific basis for exploring the molecular mechanism of immune dysfunction caused by acute BVDV infection.