title: Targeting Antigen to Clec9A Primes Follicular Th Cell Memory Responses Capable of Robust Recall.
abstract: Targeting Ags to dendritic cell (DC) surface receptors can induce a variety of responses depending on the DC type targeted, the receptor targeted, and the adjuvant used. Clec9A (DNGR-1), which is expressed by CD8(+) DCs, has been shown to bind F-actin exposed on damaged cells. Targeting Ag to this receptor in mice and nonhuman primates induces strong humoral immunity even in the absence of adjuvant, a process seen for a few select DC receptors. In contrast with other receptors, however, targeting Clec9A induces long-lived, affinity-matured Ab responses that are associated with efficient CD4(+) T cell responses shown to possess properties of follicular Th cells (TFH). In this article, we provide definitive evidence that Clec9A targeting promotes the development of TFH by showing that responding CD4 T cells express CXCR5, PD1, the TFH transcription factor Bcl6, and the cytokine IL-21, and that these cells localize to germinal centers. Furthermore, we extend studies from the model Ag OVA to the viral Ag glycoprotein D of HSV-1 and examine the capacity of primed TFH to form functional memory. We show that targeting glycoprotein D to Clec9A even in the absence of adjuvant induced long-lived memory CXCR5(+) PD1(hi) CD4(+) T cells that proliferated extensively upon secondary challenge and rapidly developed into effector TFH. This was associated with enhanced germinal center B cell responses and accelerated Ab production. Our study indicates that targeting Ags to Clec9A in the absence of adjuvant routinely generates TFH responses that form long-lived memory capable of robust secondary TFH responses.
authors.affiliation: Department of Microbiology and Immunology, The Peter Doherty Institute, The University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Yu
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Department of Microbiology and Immunology, The Peter Doherty Institute, The University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Ali
authors.initials: A
authors.lastname: Zaid
authors.affiliation: Department of Microbiology and Immunology, The Peter Doherty Institute, The University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Gayle M
authors.initials: GM
authors.lastname: Davey
authors.affiliation: Department of Microbiology and Immunology, The Peter Doherty Institute, The University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Scott N
authors.initials: SN
authors.lastname: Mueller
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nutt
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Dimitra
authors.initials: D
authors.lastname: Zotos
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: David M
authors.initials: DM
authors.lastname: Tarlinton
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Ken
authors.initials: K
authors.lastname: Shortman
authors.affiliation: Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria 3004, Australia; and Department of Immunology, Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Mireille H
authors.initials: MH
authors.lastname: Lahoud
authors.affiliation: Department of Microbiology and Immunology, The Peter Doherty Institute, The University of Melbourne, Parkville, Victoria 3010, Australia; caminschi@burnet.edu.au wrheath@unimelb.edu.au.
authors.forename: William R
authors.initials: WR
authors.lastname: Heath
authors.affiliation: Department of Microbiology and Immunology, The Peter Doherty Institute, The University of Melbourne, Parkville, Victoria 3010, Australia; Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria 3004, Australia; and caminschi@burnet.edu.au wrheath@unimelb.edu.au.
authors.forename: Irina
authors.initials: I
authors.lastname: Caminschi
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology*; D053738:Interleukin-21 Receptor alpha Subunit / Q000235:genetics; D007378:Interleukins / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis; D051560:Proto-Oncogene Proteins c-bcl-6; D054380:Receptors, CXCR5 / Q000096:biosynthesis; D011971:Receptors, Immunologic / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D014759:Viral Envelope Proteins / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D000941:Antigens; C490010:Bcl6 protein, mouse; C513179:CXCR5 protein, mouse; C529914:Clec9a protein, mouse; D004268:DNA-Binding Proteins; C508118:Il21r protein, mouse; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D037181:Lectins, C-Type; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D051560:Proto-Oncogene Proteins c-bcl-6; D054380:Receptors, CXCR5; D011971:Receptors, Immunologic; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1; D010047:Ovalbumin; D000098546:Interleukin-21