Bet v 1–specific T-cell receptor/forkhead box protein 3 transgenic T cells suppress Bet v 1–specific T-cell effector function in an activation-dependent manner - 10/08/11
Reprint requests: Winfried F. Pickl, MD, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, A-1090 Borschkegasse 8A, Vienna, Austria.Abstract |
Background |
Regulatory T (Treg) cells establish and maintain tolerance to self-antigens and many foreign antigens, such as allergens, by suppressing effector T-cell proliferation and function. We have previously shown that human T-cell receptor (TCR) ⍺β-chains specific for allergen-derived epitopes confer allergen specificity on peripheral blood T cells of individuals with and without allergy.
Objective |
To study the feasibility of generating allergen-specific human Treg cells by retroviral transduction of a transcription unit encoding forkhead box protein 3 (FOXP3) and allergen-specific TCR ⍺β-chains.
Methods |
cDNAs encoding the ⍺ and β−chains of a Bet v 1142-153−specific TCR (TCR alpha variable region 6/TCR beta variable region 20) and human FOXP3 were linked via picornaviral 2A sequences and expressed as single translational unit from an internal ribosomal entry site—green fluorescence protein−containing retroviral vector. Retrovirally transduced peripheral blood T cells were tested for expression of transgenes, Treg phenotype, and regulatory capacity toward allergen-specific effector T cells.
Results |
Transduced T cells displayed a Treg phenotype with clear-cut upregulation of CD25, CD39, and cytotoxic T-lymphocyte antigen 4. The transduced cells were hyporesponsive in cytokine production and secretion and, like naturally occurring Treg cells, did not proliferate after antigen-specific or antigen-mimetic stimulation. However, proliferation was inducible upon exposure to exogenous IL-2. In coculture experiments, TRAV6+TRBV20+FOXP3+ transgenic T cells, unlike FOXP3+ single transgenic T cells or naturally occurring Treg cells, highly significantly suppressed T cell cytokine production and proliferation of corresponding allergen-specific effector T cells in an allergen-specific, dose-dependent manner.
Conclusion |
We demonstrate a transgenic approach to engineer human allergen-specific Treg cells that exert their regulatory function in an activation-dependent manner. Customized Treg cells might become useful for tolerance induction therapies in individuals with allergic and other immune-mediated diseases.
Le texte complet de cet article est disponible en PDF.Key words : Immune regulation, regulatory T cells, allergen-specific T-cell receptor, FOXP3, type I allergy, birch pollen, Bet v 1
Abbreviations used : aAPC, FOXP3, GFP, IRES, nTreg, PB, TCR, Treg
Plan
| Supported by grants from the Austrian Science foundation (SFB F1816-B13, SFB F1807-B13, and FWF 20011-B13), the Österreichische Forschungsförderungsgesellschaft #812079 and Biomay AG, and the Christian Doppler Research Association, Austria. |
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| Disclosure of potential conflict of interest: B. Jahn-Schmid receives research support from the Austrian Science Fund. B. Bohle receives research support from the Austrian Science Fund and the Christian Doppler Laboratory. The rest of the authors have declared that they have no conflict of interest. |
Vol 127 - N° 1
P. 238 - janvier 2011 Retour au numéro
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