Feline programmed death and its ligand: characterization and changes with feline immunodeficiency virus infection.

Programmed death (PD)-1 and its ligand, PD-L1, are co-stimulatory molecules expressed on T cells and antigen-presenting cells, respectively, that modulate T cell receptor signals. Altered PD expression or signalling contributes to pathogen persistence in chronic infections. The sequence of the feline PD genes was derived from gene amplification with primers conserved across human and canine homologs, and by sequence extension through rapid amplification of cDNA ends. Feline PD-1 was similar to that of other mammalian species and consisted of extracellular, transmembrane and cytoplasmic regions. Functional motif analysis of the translated amino acid sequence predicted immunoreceptor tyrosine-based inhibitory and switch motifs, and a SH3-binding region, in the cytoplasmic tail. PD-1 and PD-L1 were expressed in resting lymphocytes and dendritic cells, and up-regulated on mitogen-activated or irradiated lymphocytes of both CD4 and CD8-positive subsets. In vitro infection with the feline immunodeficiency virus (FIV) significantly decreased PD-1, but not PD-L1, gene expression in lymphocytes at 24h, and decreased expression of both genes at 168h. No significant changes in gene or protein expression from FIV infection were noted in dendritic cells. Blood lymphocytes from cats chronically FIV-infected expressed significantly higher PD protein than lymphocytes from FIV-negative cats. These findings indicate that both feline PD-1 and PD-L1 are expressed by resting lymphocytes and dendritic cells. Apoptosis and cell activation increased protein expression on lymphocytes, while in vitro acute FIV infection decreased PD-1 gene expression. Increased PD levels in lymphocytes from chronically FIV-infected cats suggests that alterations in T cell co-signalling may contribute to immune dysfunction in lentiviral infection.

Structure and function of programmed death (PD) molecules.

Programmed death (PD) molecules belong to the B7 family of co-stimulatory proteins and function in adaptive immunity. PD-1 (CD279) is expressed on lymphocytes and macrophages, and its ligand (PD-L1, CD274) on immune cells and non-hematopoietic cells. Ligation of PD-1 on lymphocytes inhibits T-cell proliferation, cytokine production, and cytolytic function by phosphorylation of immunoreceptor tyrosine-based switch motifs and blockade of T cell receptor signaling. PD-1 and PD-L1 interactions are essential to maintain peripheral immune tolerance and to modulate activation of naïve T cells. Decreased expression results in autoimmunity in mouse models, and increased expression is a key feature of chronic viral infections in humans.