IHV > Research : Natural T Regulatory Cells in the Pathogenesis of Severe Chronic Diseases
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Natural T Regulatory Cells in the Pathogenesis of Severe Chronic Diseases

Lab Head

Daniel Zagury
Daniel Zagury

Associated Faculty

Helene Le Buanec 
Hélène Le Buanecgallo175
Professor Robert Gallo, MD 

Naturally occuring T regulatory cells (nTreg) control host immune responses against self and foreign antigens, including commensal microorganism and dietary molecules. They silence autoreactive T cells but also modulate/suppress pathogen-specific effector -cell functions such as CD4 helper producing immunostimulatory cytokines, CD8 cytotoxic and antibody secreting B cells. Identified by the pioneering work of Sakaguchi et al, thymus-derived nTreg cells are characterized by the CD4+CD25highCD127lo/- phenotype, the constitutive expression of the transcription factor Foxp3 and an incapacity to synthesize IL-2. These cells exert their functional suppressive activity towards autoreactive cells through a cell-contact-dependent Treg/APC/T cell interactions (self tolerance). However these cells possess a functional plasticity dependent on cytokine milieu.

The dysfunction of these cells is critical in the pathogenesis of severe chronic diseases including autoimmunity, cancer and viral infections. Reduced functional activity of nTreg cells results in an increased susceptibility to autoimmune diseases. Elevated numbers of nTreg cells at the tumor site impairs the host anti-tumoral cellular immune response. In chronic viral infections (HBV,HCV and HIV), enhanced Treg frequency and activity are beneficial or detrimental depending on the circumstances.

The causes of nTreg dysfunction are as yet confusing and the mechanisms have to be investigated for each pathology.

Given their functional variability, it is important to manage cautiously novel therapies based on nTreg adoptive administration, nTreg depletion or cytokine administration in order to avoid undesirable outcome.

Selected Publications:

Zagury D., Le Buanec H., Mathian A., Larcier P., Burnett R., Amoura Z., Emilie D., Peltre G., Bensussan A., Bizzini B., Gallo R.C., Koutouzov S. IFNα kinoid vaccine-induced neutralizing antibodies prevent clinical manifestations in a lupus flare murine model. Proc Natl Acad Sci U S A. 2009:5294-5299.

Delavallée L*, Le Buanec H*, Bessis N, Assier E, Denys A, Bizzini B, Zagury D, Boissier MC.Early and long-lasting protection from arthritis in TNF{alpha} transgenic mice vaccinated against TNF{alpha}, Ann Rheum Dis, 2008, 67:1332-8.

Le Buanec H*, Paturance S, Couillin I, Schnyder-Candrian S, Larcier P, Ryffel B, Bizzini B, Bensussan A, Burny A, Gallo RC, Zagury D, Peltre G, Control of allergic reactions in mice by an active anti-murine IL-4 immunization, Vaccine. 2007, 25:7206-16

Haghighi Rad F*, Le Buanec H*, Paturance S, Larcier P, Guilbaud N,Ryffel B, Bizzini B, Gallo R.C, Zagury D and Uzan G. 2007. VEGF kinoid vaccine, a therapeutic arm against tumor angiogenesis and metastases, Proc Natl Acad Sci U S A, 104:2837-42

Le Buanec H*, Delavallée L*, Bessis N, Paturance S, Bizzini B, Gallo RC, Zagury D, Boissier MC. 2006 Neutralizing Abs to TNFα induced by TNFα-Kinoid vaccination, an alternative to anti-TNFα monoclonal Ab therapy. Proc Natl Acad Sci U S A, 103:19442-7

Zagury D, Le Buanec H, Bizzini B, Burny A, Lewis G, Gallo RC (2003). Active versus passive anti-cytokine antibody therapy against cytokine-associated chronic diseases. Cytokine Growth Factor Rev. 14:123-37.