title: Ex vivo enzymatic treatment of aged CD4 T cells restores cognate T cell helper function and enhances antibody production in mice.
abstract: Previous in vitro studies showed that CD4 T cells from old mice have defects in TCR signaling, immune synapse formation, activation, and proliferation. We reported that removing a specific set of surface glycoproteins by ex vivo treatment with O-sialoglycoprotein endopeptidase (OSGE) can reverse many aspects of the age-related decline in CD4 T cell function. However, the specific mechanism by which this process occurs remains unclear, and it is unknown whether this enzymatic treatment can also restore important aspects of adaptive immunity in vivo. By using an in vivo model of the immune response based on adoptive transfer of CD4 T cells from pigeon cytochrome C-specific transgenic H-2(k/k) TCR-Vα(11)Vβ(3) CD4(+) mice to syngeneic hosts, we demonstrate that aging diminishes CD28 costimulatory signals in CD4 T cells. These age-associated defects include changes in phosphorylation of AKT and expression of glucose transporter type I, inducible T cell costimulatory molecule, and CD40L, suggesting that the lack of CD28 costimulation contributes to age-dependent loss of CD4 function. All of these deficits can be reversed by ex vivo OSGE treatment. Blocking B7-CD28 interactions on T cells prevents OSGE-mediated restoration of T cell function, suggesting that changes in surface glycosylation, including CD28, may be responsible for the age-related costimulation decline. Finally, we show that the age-related decline in CD4 cognate helper function for IgG production and long-term humoral immunity can also be restored by OSGE treatment of CD4 T cells prior to adoptive transfer.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan College of Literature, Science and the Arts, Ann Arbor, MI 48109, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Perkey
authors.forename: Richard A
authors.initials: RA
authors.lastname: Miller
authors.forename: Gonzalo G
authors.initials: GG
authors.lastname: Garcia
mesh_terms: D019264:Adoptive Transfer; D000375:Aging / Q000187:drug effects / Q000276:immunology; D000818:Animals; D000918:Antibody Specificity / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000187:drug effects / Q000276:immunology*; D007074:Immunoglobulin G / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000276:immunology; D008666:Metalloendopeptidases / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*
chemical_list: D007074:Immunoglobulin G; D008666:Metalloendopeptidases; C070738:O-sialoglycoprotein endopeptidase