Programmed death‐ligand 1 expression in swine chronic infections and enhancement of interleukin‐2 production via programmed death‐1/programmed death‐ligand 1 blockade

Abstract

Introduction Chronic infections lead to the functional exhaustion of T cells. Exhausted T cells are phenotypically differentiated by the surface expression of the immunoinhibitory receptor, such as programmed death‐1 (PD‐1). The inhibitory signal is produced by the interaction between PD‐1 and its PD‐ligand 1 (PD‐L1) and impairs the effector functions of T cells. However, the expression dynamics of PD‐L1 and the immunological functions of the PD‐1/PD‐L1 pathway in chronic diseases of pigs are still poorly understood. In this study, we first analyzed the expression of PD‐L1 in various chronic infections in pigs, and then evaluated the immune activation by the blocking assay targeting the swine PD‐1/PD‐L1 pathway. Methods In the initial experiments, anti‐bovine PD‐L1 monoclonal antibodies (mAbs) were tested for cross‐reactivity with swine PD‐L1. Subsequently, immunohistochemical analysis was conducted using the anti‐PD‐L1 mAb. Finally, we assessed the immune activation of swine peripheral blood mononuclear cells (PBMCs) by the blockade with anti‐PD‐L1 mAb. Results Several anti‐PD‐L1 mAbs tested recognized swine PD‐L1‐expressing cells. The binding of swine PD‐L1 protein to swine PD‐1 was inhibited by some of these cross‐reactive mAbs. In addition, immunohistochemical analysis revealed that PD‐L1 was expressed at the site of infection in chronic infections of pigs. The PD‐L1 blockade increased the production of interleukin‐2 from swine PBMCs. Conclusions These findings suggest that the PD‐1/PD‐L1 pathway could be also involved in immunosuppression in chronic infections in pigs. This study provides a new perspective on therapeutic strategies for chronic diseases in pigs by targeting immunosuppressive pathways.

Enhancement of Vaccine-Induced T-Cell Responses by PD-L1 Blockade in Calves

“…The combination of viral vaccination and PD-L1 blockade may enhance vaccine efficacy and reduce the number of calf deaths due to pneumonia and diarrhea, thereby improving dairy and beef cattle productivity. In addition, T-cell exhaustion via the PD-1/PD-L1 pathway is a conserved immune regulatory mechanism from domestic and companion animals to humans [ 2 , 5 , 6 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. Accordingly, this strategy may increase the efficacy of vaccination programs across a wide range of animal species, not just in cattle.…”

The PD-1/PD-L1 Pathway: A Perspective on Comparative Immuno-Oncology

“…In farm animals, these studies have mainly centered on chronic infectious diseases due to their economic relevance [ 65 , 66 , 67 , 74 , 75 ], whereas in companion animals, investigations have focused on canine cancer [ 64 , 77 , 79 , 81 ]. Notably, the estimated annual cancer rate in dogs is higher than that in human beings.…”

“…These include anti-canine PD-1 [ 63 ], anti-canine PD-L1 [ 63 , 64 ], anti-bovine PD-L1 [ 65 ], and anti-bovine PD-1 [ 66 ]. Anti-bovine PD-L1 antibody shows cross-reactivity with porcine PD-L1 [ 67 ] and canine PD-L1 [ 68 ]. In addition, cross-reactive anti-human PD-1, PD-L1, or PD-L2 antibodies were used in canine [ 69 ], equine [ 70 ], and feline tissues [ 71 ].…”

“…In pigs, an increase in PD-L1 immunostaining has been described in tissue samples of pigs with chronic diseases, i.e., infection with Mycoplasma hyopneumoniae, Lawsonia intracellularis, and porcine circovirus 2, compared to uninfected tissue from a control pig [ 67 ].…”