Tregs utilize beta-galactoside-binding protein to transiently inhibit PI3K/p21ras activity of human CD8+ T cells to block their TCR-mediated ERK activity and proliferation.
Regulatory T cells (Tregs) and beta-galactoside-binding protein (betaGBP), a regulatory protein often found expressed at sites of immunological privilege, have similar functions. Their presence affects the outcome of harmful autoimmunity and cancers, including experimental autoimmune encephalomyelitis and malignant gliomas. Here we report a novel pathway by which Tregs express and utilize betaGBP to control CD8(+) T cell responses partially activating TCR signaling but blocking PI3K activity. As a result, this leads to a loss of p21(ras), ERK and Akt activities despite activation of TCR proximal signals, such as phosphorylation of CD3zeta, Zap70, Lat and PKCtheta. Although non-processive TCR signaling often leads to cell anergy, Tregs/betaGBP did not affect cell viability. Instead, betaGBP/Tregs transiently prevented activation of CD8(+) T cells with self-antigens, while keeping their responses to xenogeneic antigens unaffected.
Baatar
Dolgor
D
Immunotherapeutics Unit, Laboratory of Immunology, National Institute on Aging, Baltimore, MD 21224, USA.
Olkhanud
Purevdorj B
PB
Wells
Valerie
V
Indig
Fred E
FE
Mallucci
Livio
L
Biragyn
Arya
A
D001324:Autoantigens / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D037483:Galectin 1 / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018613:Microscopy, Confocal; D010766:Phosphorylation / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D018631:ras Proteins / Q000276:immunology / Q000378:metabolism
D001324:Autoantigens; D037483:Galectin 1; D011948:Receptors, Antigen, T-Cell; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins