title: Circulating CXCR5+CXCR3+PD-1loTfh-like cells in HIV-1 controllers with neutralizing antibody breadth.
abstract: HIV-1-specific broadly neutralizing antibodies (bnAbs) typically develop in individuals with continuous high-level viral replication and increased immune activation, conditions that cannot be reproduced during prophylactic immunization. Understanding mechanisms supporting bnAb development in the absence of high-level viremia may be important for designing bnAb-inducing immunogens. Here, we show that the breadth of neutralizing antibody responses in HIV-1 controllers was associated with a relative enrichment of circulating CXCR5+CXCR3+PD-1loCD4+T cells. These CXCR3+PD-1loTfh-like cells were preferentially induced in vitro by functionally superior dendritic cells from controller neutralizers, and able to secrete IL-21 and support B cells. In addition, these CXCR3+PD-1loTfh-like cells contained higher proportions of stem cell-like memory T cells, and upon antigenic stimulation differentiated into PD-1hiTfh-like cells in a Notch-dependent manner. Together, these data suggest that CXCR5+CXCR3+PD-1locells represent a dendritic cell-primed precursor cell population for PD-1hiTfh-like cells that may contribute to the generation of bnAbs in the absence of high-level viremia.
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Enrique
authors.initials: E
authors.lastname: Martin-Gayo
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cronin
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Hickman
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Ouyang
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), Duke University, Durham, North Carolina, USA.
authors.forename: Madelene
authors.initials: M
authors.lastname: Lindqvist
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.|MIT Institute for Medical Engineering & Science (IMES) and Chemistry, Cambridge, Massachusetts, USA.
authors.forename: Kellie E
authors.initials: KE
authors.lastname: Kolb
authors.affiliation: University Medical Center Hamburg, Hamburg, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Schulze Zur Wiesch
authors.affiliation: Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Cubas
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Filippos
authors.initials: F
authors.lastname: Porichis
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.|MIT Institute for Medical Engineering & Science (IMES) and Chemistry, Cambridge, Massachusetts, USA.
authors.forename: Alex K
authors.initials: AK
authors.lastname: Shalek
authors.affiliation: University Medical Center Hamburg, Hamburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: van Lunzen
authors.affiliation: Drexel University, Division of Infectious Diseases and HIV Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Elias K
authors.initials: EK
authors.lastname: Haddad
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), Duke University, Durham, North Carolina, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), Duke University, Durham, North Carolina, USA.|Centre hospitalier de l'Université de Montréal (CHUM) Research Center, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.|Infectious Disease Divisions, Brigham and Women's Hospital and Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Mathias
authors.initials: M
authors.lastname: Lichterfeld
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Xu G
authors.initials: XG
authors.lastname: Yu
mesh_terms: D016915:AIDS Vaccines; D019380:Anti-HIV Agents / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001402:B-Lymphocytes; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells; D060467:Disease Resistance / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D066298:In Vitro Techniques; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000276:immunology / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D014766:Viremia / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D016915:AIDS Vaccines; D019380:Anti-HIV Agents; D057134:Antibodies, Neutralizing; C515187:CXCR3 protein, human; C095085:CXCR5 protein, human; D015483:HIV Antibodies; D007378:Interleukins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D054367:Receptors, CXCR3; D054380:Receptors, CXCR5; D000098546:Interleukin-21