Increased T-cell reactivity and elevated levels of CD8+ memory T-cells in Alzheimer's disease-patients and T-cell hyporeactivity in an Alzheimer's disease-mouse model: implications for immunotherapy.
Neuroinflammation is observed in neurodegenerative diseases like Alzheimer's disease (AD). However, a little is known about the mechanisms of neural-immune interactions. The involvement of peripheral T-cell function in AD is still far from clear, though it plays an important role in immunotherapy. The aim of this study was to determine peripheral T-cell reactivity in AD patients and in an AD mouse model. Mitogenic activation via ligation of the T-cell receptor (TCR) with PHA-L was measured in T lymphocytes from AD patients and Thy1(APP 751SL) x HMG(PS1 M146L)-transgenic mice (APP x PS1). In order to uncover failures in TCR signaling, the TCR was also bypassed by PMA and ionomycin treatment. All patients were sporadic late onset cases and the transgenic mice expressed no mutant APP in lymphocytes, so that direct interactions of mutant APP on T-cell function can be excluded. CD4+ and CD8+ T-cell showed increased reactivity (tyrosine phosphorylation, CD69 expression, and proliferation) in AD, while APP x PS1 transgenic mice displayed hyporeactive CD8+ T-cells after TCR ligation. Increased levels of CD8+ T memory cells and down regulation of CD8 receptor were found in AD and the animal model. Anergic TCR uncoupling was associated with loss of MAPK signaling (p38, ERK1 and ERK2) in APP x PS1. Our data implicate the generation of reactive memory T-cell in AD and of anergic memory T-cells in transgenic mice and should be taken into concern when designing immunotherapy.
Schindowski
Katharina
K
Institute of Pharmacology, Biocenter building N260, Johann Wolfgang-Goethe-University, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany. Katharina.Schindowski@lille.inserm.fr
Eckert
Anne
A
Peters
Jürgen
J
Gorriz
Corinna
C
Schramm
Uta
U
Weinandi
Thomas
T
Maurer
Konrad
K
Frölich
Lutz
L
Müller
Walter E
WE
D000368:Aged; D000544:Alzheimer Disease / Q000276:immunology*; D000818:Animals; D001057:Apolipoproteins E / Q000097:blood / Q000235:genetics; D016516:CD4-CD8 Ratio; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory; D007167:Immunotherapy / Q000379:methods*; D007963:Leukocytes, Mononuclear / Q000502:physiology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019000:Phosphotyrosine / Q000378:metabolism
D001057:Apolipoproteins E; D019000:Phosphotyrosine