title: Soluble PD-1 is associated with aberrant regulation of T cells activation in aplastic anemia.
abstract: Engagement of the membrane program death-1 (PD-1) receptor by its ligands suppresses T cell proliferation and cytokine production. Aberrant over-expression of costimulatory molecules, including PD-1, has been associated with persistent activation of self-reactive T cells in autoimmune diseases. However, the mechanism underlying the dysfunction of PD-1 in the regulation of T-cell activation in such diseases remains unclear. Here, we report the overexpression of CD4(+) and CD8(+) T cell PD-1 and elevated serum levels of soluble PD-1 in aplastic anemia (AA) patients. Detailed characterization of soluble PD-1 revealed that it corresponded to an alternative splice variant PD-1Deltaex3, which lacks the transmembrane domain but has a soluble extracellular domain of the PD-1 molecule. In a further study, PD-1 fusion protein displayed the ability of increasing the proliferation of T cells in vitro, which suggested that soluble PD-1 might serve as an autoimmune antibody to block the function of membrane-bound PD-1 on T cells and lead to aberrant T cell proliferation. Our study revealed a novel pathogenic pathway in which the function of overexpressed PD-1 to restrict over-self-reaction is counteracted by the excessive production of soluble PD-1.
authors.affiliation: College of Pharmacy, School of Medicine, Soochow University, Suzhou, China.
authors.forename: Haijing
authors.initials: H
authors.lastname: Wu
authors.forename: Miao
authors.initials: M
authors.lastname: Miao
authors.forename: Guangbo
authors.initials: G
authors.lastname: Zhang
authors.forename: Yumin
authors.initials: Y
authors.lastname: Hu
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Ming
authors.forename: Xueguang
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000741:Anemia, Aplastic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D061026:Programmed Cell Death 1 Receptor; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D020033:Protein Isoforms