title: TLR-9 signaling and TCR stimulation co-regulate CD8(+) T cell-associated PD-1 expression.
abstract: Elevated Programmed Death-1 (PD-1) expression can inhibit T cell activity and is a potential barrier to achieving persisting and optimal immunity via therapeutic vaccination. Using a direct lymph node-targeted vaccination procedure that enabled uncoupling of synthetic peptide (signal 1, TCR-mediated) and adjuvant (signal 2, non-TCR-mediated), we evaluated the impact of varied doses of Toll-like receptor (TLR)-9 ligand CpG oligodeoxynucleotide (ODN) adjuvant on epitope-specific CD8(+) T cell-associated PD-1 expression. Peptide vaccination without adjuvant yielded CD8(+) T cells with significantly elevated PD-1 expression. This conferred impaired function ex vivo, but was reversible by antibody-mediated PD-1 blockade. By comparison, peptide vaccination with escalating doses of CpG ODN adjuvant yielded higher magnitudes of CD8(+) T cells with progressively lower PD-1 expression and greater ex vivo function. CpG ODN adjuvant in context of titrated peptide doses for vaccination yielded the lowest overall PD-1 expression levels, demonstrating that fine-tuning both TCR-independent (adjuvant dose) and -dependent (antigen dose) stimuli can synergize to co-regulate PD-1 expression on epitope-specific CD8(+) T cells. These data hint at strategies to elicit PD-1(low) CD8(+) T cells using TLR-9 ligand adjuvants, and also shed light on the PD-1-regulated homeostasis of CD8(+) T cells.
authors.affiliation: MannKind Corporation, 28903 Avenue Paine, Valencia, CA, USA.
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Wong
authors.forename: Kent A
authors.initials: KA
authors.lastname: Smith
authors.forename: Victor L
authors.initials: VL
authors.lastname: Tam
authors.forename: Robb R
authors.initials: RR
authors.lastname: Pagarigan
authors.forename: Brenna L
authors.initials: BL
authors.lastname: Meisenburg
authors.forename: Angeline M
authors.initials: AM
authors.lastname: Quach
authors.forename: Mayra A
authors.initials: MA
authors.lastname: Carrillo
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Qiu
authors.forename: Adrian I
authors.initials: AI
authors.lastname: Bot
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D004247:DNA / Q000008:administration & dosage; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D015234:HLA-A Antigens / Q000235:genetics; D015789:HLA-A2 Antigen; D007114:Immunization; D008024:Ligands; D058965:MART-1 Antigen; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000276:immunology; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; C423449:CpG ODN 1826; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D008024:Ligands; D058965:MART-1 Antigen; C548668:Mlana protein, mouse; D009363:Neoplasm Proteins; D009838:Oligodeoxyribonucleotides; C491383:Pdcd1 protein, mouse; D010446:Peptide Fragments; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D051217:Toll-Like Receptor 9; D004247:DNA