Defective T cell priming associated with aging can be rescued by signaling through 4-1BB (CD137).
Aging is associated with an increased susceptibility to infectious agents and correlates with a decreased ability to mount an immune response. It has been postulated that the major defect is related to a reduced capacity of an aged T cell to proliferate and to survive after encounter with Ag. This is similar to the phenotype associated with T cell tolerance in young adults. In this study, we determined whether targeting 4-1BB (CD137), a member of the TNFR family implicated in providing expansion and survival signals to T cells, can rescue defective priming in aged and tolerized animals. Agonist Abs to 4-1BB injected in vivo were capable of preventing CD4 T cell tolerance to soluble peptide in young mice. Moreover, anti-4-1BB rescued defective priming of aged TCR transgenic CD4 T cells responding to peptide Ag in a young host, and as importantly, anti-4-1BB completely restored T cell priming to protein Ag in nontransgenic aged mice. These studies demonstrate that 4-1BB, and potentially other costimulatory members of the TNFR family, are targets for therapies aimed at augmenting weak T cell responses in elderly immunocompromised individuals.
Bansal-Pakala
Pratima
P
Division of Immunochemistry, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
Croft
Michael
M
D019264:Adoptive Transfer; D000375:Aging / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD; D018106:CD28 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D002678:Chimera / Q000276:immunology; D003574:Cytochrome c Group / Q000276:immunology; D007106:Immune Sera / Q000008:administration & dosage; D007108:Immune Tolerance / Q000235:genetics; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009036:Moths / Q000276:immunology; D017475:Receptors, Nerve Growth Factor / Q000819:agonists / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D012995:Solubility; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D015703:Antigens, CD; D018106:CD28 Antigens; D003574:Cytochrome c Group; D007106:Immune Sera; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9