B7-H1 expression on old CD8+ T cells negatively regulates the activation of immune responses in aged animals.
T cell responses are compromised in the elderly. The B7-CD28 family receptors are critical in the regulation of immune responses. We evaluated whether the B7-family and CD28-family receptors were differentially expressed in dendritic cells, macrophages, and CD4(+) and CD8(+) T cells from young and old mice, which could contribute to the immune dysfunction in the old. Although most of the receptors were equally expressed in all cells, >85% of the old naive CD8(+) T cells expressed B7-H1 compared with 25% in the young. Considering that B7-H1 negatively regulates immune responses, we hypothesized that expression of B7-H1 would downregulate the function of old CD8(+) T cells. Old CD8(+) T cells showed reduced ability to proliferate, but blockade of B7-H1 restored the proliferative capacity of old CD8(+) T cells to a level similar to young CD8(+) T cells. In vivo blockade of B7-H1 restored antitumor responses against the B7-H1(-) BM-185-enhanced GFP tumor, such that old animals responded with the same efficiency as young mice. Our data also indicate that old CD8(+) T cells express lower levels of TCR compared with young CD8(+) T cells. However, following antigenic stimulation in the presence of B7-H1 blockade, the levels of TCR expression were restored in old CD8(+) T cells, which correlated with stronger T cell activation. These studies demonstrated that expression of B7-H1 in old CD8(+) T cells impairs the proper activation of these cells and that blockade of B7-H1 could be critical to optimally stimulate a CD8 T cell response in the old.
Mirza
Noweeda
N
Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, AZ 85259.
Duque
Maria Adelaida
MA
Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, AZ 85259.
Dominguez
Ana Lucia
AL
Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, AZ 85259.
Schrum
Adam G
AG
Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic Rochester, Rochester, MN 55905.
Dong
Haidong
H
Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic Rochester, Rochester, MN 55905.
Lustgarten
Joseph
J
Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, AZ 85259.
D000375:Aging / Q000276:immunology*; D000818:Animals; D000954:Antigens, Surface / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D018122:B7-1 Antigen / Q000096:biosynthesis* / Q000502:physiology; D060890:B7-H1 Antigen; D018106:CD28 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D018655:Lymphocyte Count; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000037:antagonists & inhibitors / Q000502:physiology; D061026:Programmed Cell Death 1 Receptor
D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D018106:CD28 Antigens; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor