Lethal T cell immunodeficiency induced by chronic costimulation via CD27-CD70 interactions.
It has been proposed that HIV-1, in addition to directly infecting and killing CD4+ T cells, causes T cell dysfunction and T cell loss by chronic immune activation. We analyzed the effects of chronic immune activation in mice that constitutively expressed CD70, the ligand for the tumor necrosis factor receptor family member CD27, on B cells. CD70 transgenic (CD70 Tg) mice showed a progressive conversion of naive T cells into effector-memory cells, which culminated in the depletion of naive T cells from lymph nodes and spleen. T cell changes depended on continuous CD27-CD70 interactions and T cell antigen receptor stimulation. Despite this hyperactive immune system, CD70 Tg mice died aged 6-8 months from Pneumocystis carinii infection, a hallmark of T cell immunodeficiency. Thus, persistent delivery of costimulatory signals via CD27-CD70 interactions, as may occur during chronic active viral infections, can exhaust the T cell pool and is sufficient to induce lethal immunodeficiency.
Tesselaar
Kiki
K
Laboratory for Experimental Immunology, Academic Medical Center, P.O. Box 22700, 1100DD Amsterdam, The Netherlands.
Arens
Ramon
R
van Schijndel
Gijs M W
GM
Baars
Paul A
PA
van der Valk
Martin A
MA
Borst
Jannie
J
van Oers
Marinus H J
MH
van Lier
René A W
RA
D000818:Animals; D015703:Antigens, CD; D053282:CD27 Ligand; D003588:Cytopathogenic Effect, Viral; D015658:HIV Infections / Q000209:etiology / Q000276:immunology; D015497:HIV-1 / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011020:Pneumonia, Pneumocystis / Q000209:etiology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism*
D015703:Antigens, CD; D053282:CD27 Ligand; C505771:CD70 protein, human; C505772:Cd70 protein, mouse; D008565:Membrane Proteins; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7