title: Inadequate T follicular cell help impairs B cell immunity during HIV infection.
abstract: The majority of HIV-infected individuals fail to produce protective antibodies and have diminished responses to new immunizations. We report here that even though there is an expansion of follicular helper T (TFH) cells in HIV-infected individuals, the cells are unable to provide adequate B cell help. We found a higher frequency of programmed cell death ligand 1 (PD-L1)(+) germinal center B cells from lymph nodes of HIV-infected individuals suggesting a potential role for PD-1-PD-L1 interaction in regulating TFH cell function. In fact, we show that engagement of PD-1 on TFH cells leads to a reduction in cell proliferation, activation, inducible T-cell co-stimulator (ICOS) expression and interleukin-21 (IL-21) cytokine secretion. Blocking PD-1 signaling enhances HIV-specific immunoglobulin production in vitro. We further show that at least part of this defect involves IL-21, as addition of this cytokine rescues antibody responses and plasma cell generation in vitro. Our results suggest that deregulation of TFH cell-mediated B cell help diminishes B cell responses during HIV infection and may be related to PD-1 triggering on TFH cells. These results demonstrate a role for TFH cell impairment in HIV pathogenesis and suggest that enhancing their function could have a major impact on the outcome and control of HIV infection, preventing future infections and improving immune responses to vaccinations.
authors.affiliation: Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA.
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Cubas
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Mudd
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Savoye
authors.forename: Matthieu
authors.initials: M
authors.lastname: Perreau
authors.forename: Julien
authors.initials: J
authors.lastname: van Grevenynghe
authors.forename: Talibah
authors.initials: T
authors.lastname: Metcalf
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Connick
authors.forename: Amie
authors.initials: A
authors.lastname: Meditz
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Guillermo
authors.initials: G
authors.lastname: Abesada-Terk
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Jacobson
authors.forename: Ari D
authors.initials: AD
authors.lastname: Brooks
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Estes
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pantaleo
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lederman
authors.forename: Elias K
authors.initials: EK
authors.lastname: Haddad
mesh_terms: D000328:Adult; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000502:physiology; D060890:B7-H1 Antigen / Q000502:physiology; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007378:Interleukins / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology / Q000502:physiology; D008253:Macaca mulatta; D008297:Male; D008875:Middle Aged; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000502:physiology; D000098546:Interleukin-21
chemical_list: D060890:B7-H1 Antigen; D007074:Immunoglobulin G; D007378:Interleukins; D000098546:Interleukin-21