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ABSTRACTMycoplasma bovis-induced immune suppression is a major obstacle faced by the host for controlling infections. M. bovisimpairment of antigen-specific T-cell responses is achieved through inhibiting the proliferation of peripheral blood mononuclear cells (PBMCs). This impairment may contribute to the persistence of M. bovisinfection in various sites, including lungs, and its systemic spread to various organs such as joints, with the underlying mechanisms remaining elusive. Here, we elucidated the role of the immune-inhibitory receptor programmed death 1 (PD-1) and its ligand (PD-L1) in M. bovisinfection. Flow cytometry (FCM) analyses revealed an upregulation of PD-L1 expression on tracheal and lung epithelial cell lines after M. bovisinfection. In addition, we found increased PD-L1 expression on purified lung lavage macrophages following M. bovisinfection by FCM and determined its localization by immunofluorescence analysis comparing infected and control lung tissue sections. Moreover, M. bovisinfection increased the expression of the PD-1 receptor on total PBMCs and in gated CD4+and CD8+T-cell subpopulations. We demonstrated that M. bovisinfection induced a significant decrease in CD4+PD-1INTand CD8+PD-1INTsubsets with intermediate PD-1 expression, which functioned as progenitor pools giving rise to CD4+PD-1HIGHand CD8+PD-1HIGHsubsets with high PD-1 expression levels. We blocked PD-1 receptors on PBMCs using anti-PD-1 antibody at the beginning of infection, leading to a significant restoration of the proliferation of PBMCs. Taken together, our data indicate a significant involvement of the PD-1/PD-L1 inhibitory pathway during M. bovisinfection and its associated immune exhaustion, culminating in impaired host immune responses.