title: Defective TFH Cell Function and Increased TFR Cells Contribute to Defective Antibody Production in Aging.
abstract: Defective antibody production in aging is broadly attributed to immunosenescence. However, the precise immunological mechanisms remain unclear. Here, we demonstrate an increase in the ratio of inhibitory T follicular regulatory (TFR) cells to stimulatory T follicular helper (TFH) cells in aged mice. Aged TFH and TFR cells are phenotypically distinct from those in young mice, exhibiting increased programmed cell death protein-1 expression but decreased ICOS expression. Aged TFH cells exhibit defective antigen-specific responses, and programmed cell death protein-ligand 1 blockade can partially rescue TFH cell function. In contrast, young and aged TFR cells have similar suppressive capacity on a per-cell basis in vitro and in vivo. Together, these studies reveal mechanisms contributing to defective humoral immunity in aging: an increase in suppressive TFR cells combined with impaired function of aged TFH cells results in reduced T-cell-dependent antibody responses in aged mice.
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Sage
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Tan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Marcia
authors.initials: M
authors.lastname: Haigis
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: arlene_sharpe@hms.harvard.edu.
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
mesh_terms: D000375:Aging; D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D000941:Antigens / Q000276:immunology; D018106:CD28 Antigens / Q000172:deficiency / Q000235:genetics; D056724:Immunity, Humoral; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D010581:Peyer's Patches / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*
chemical_list: D000941:Antigens; D018106:CD28 Antigens; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D061026:Programmed Cell Death 1 Receptor; D010047:Ovalbumin