title: Potentiating functional antigen-specific CD8⁺ T cell immunity by a novel PD1 isoform-based fusion DNA vaccine.
abstract: Understanding and identifying new ways of mounting an effective CD8⁺ T cell immune response is important for eliminating infectious pathogens. Although upregulated programmed death-1 (PD1) in chronic infections (such as HIV-1 and tuberculosis) impedes T cell responses, blocking this PD1/PD-L pathway could functionally rescue the "exhausted" T cells. However, there exists a number of PD1 spliced variants with unknown biological function. Here, we identified a new isoform of human PD1 (Δ42PD1) that contains a 42-nucleotide in-frame deletion located at exon 2 domain found expressed in peripheral blood mononuclear cells (PBMCs). Δ42PD1 appears to function distinctly from PD1, as it does not engage PD-L1/PD-L2 but its recombinant form could induce proinflammatory cytokines. We utilized Δ42PD1 as an intramolecular adjuvant to develop a fusion DNA vaccine with HIV-1 Gag p24 antigen to immunize mice, which elicited a significantly enhanced level of anti-p24 IgG1/IgG2a antibody titers, and important p24-specific and tetramer⁺CD8⁺ T cells responses that lasted for ≥7.5 months. Furthermore, p24-specific CD8⁺ T cells remain functionally improved in proliferative and cytolytic capacities. Importantly, the enhanced antigen-specific immunity protected mice against pathogenic viral challenge and tumor growth. Thus, this newly identified PD1 variant (Δ42PD1) amplifies the generation of antigen-specific CD8⁺ T cell immunity when used in a DNA vaccine.
authors.affiliation: AIDS Institute, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Jingying
authors.initials: J
authors.lastname: Zhou
authors.forename: Allen Kl
authors.initials: AK
authors.lastname: Cheung
authors.forename: Henggui
authors.initials: H
authors.lastname: Liu
authors.forename: Zhiwu
authors.initials: Z
authors.lastname: Tan
authors.forename: Xian
authors.initials: X
authors.lastname: Tang
authors.forename: Yuanxi
authors.initials: Y
authors.lastname: Kang
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Du
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016133:Polymerase Chain Reaction; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics; D020033:Protein Isoforms / Q000276:immunology*; D019444:Vaccines, DNA / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D020033:Protein Isoforms; D019444:Vaccines, DNA