title: IL-6 Production by TLR-Activated APC Broadly Enhances Aged Cognate CD4 Helper and B Cell Antibody Responses In Vivo.
abstract: Naive CD4 T cell responses, especially their ability to help B cell responses, become compromised with aging. We find that using APC pretreated ex vivo with TLR agonists, polyinosinic-polycytidylic acid and CpG, to prime naive CD4 T cells in vivo, restores their ability to expand and become germinal center T follicular helpers and enhances B cell IgG Ab production. Enhanced helper responses are dependent on IL-6 production by the activated APC. Aged naive CD4 T cells respond suboptimally to IL-6 compared with young cells, such that higher doses are required to induce comparable signaling. Preactivating APC overcomes this deficiency. Responses of young CD4 T cells are also enhanced by preactivating APC with similar effects but with only partial IL-6 dependency. Strikingly, introducing just the activated APC into aged mice significantly enhances otherwise compromised Ab production to inactivated influenza vaccine. These findings reveal a central role for the production of IL-6 by APC during initial cognate interactions in the generation of effective CD4 T cell help, which becomes greater with age. Without APC activation, aging CD4 T cell responses shift toward IL-6-independent Th1 and CD4 cytotoxic Th cell responses. Thus, strategies that specifically activate and provide Ag to APC could potentially enhance Ab-mediated protection in vaccine responses.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Vinayak
authors.initials: V
authors.lastname: Brahmakshatriya
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Yi
authors.identifier: 0000-0002-3266-1781
authors.initials: Y
authors.lastname: Kuang
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Priyadharshini
authors.identifier: 0000-0003-2058-6339
authors.initials: P
authors.lastname: Devarajan
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Jingya
authors.initials: J
authors.lastname: Xia
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Wenliang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Allen Minh
authors.initials: AM
authors.lastname: Vong
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605 Susan.Swain@umassmed.edu.
authors.forename: Susan L
authors.identifier: 0000-0002-3643-8018
authors.initials: SL
authors.lastname: Swain
mesh_terms: D019264:Adoptive Transfer; D000375:Aging / Q000276:immunology*; D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D005434:Flow Cytometry; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D015850:Interleukin-6; D051193:Toll-Like Receptors