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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:127

Article

Schmetterer, Klaus G.¹  Haiderer, Daniela¹  Leb-Reichl, Victoria M.^1,3  Neunkirchner, Alina^1,3  Jahn-Schmid, Beatrice²  Kueng, Hans J.¹  Schuch, Karina¹  Steinberger, Peter¹  Bohle, Barbara^2,3  Pickl, Winfried F.^1,3 

[1] Med Univ Vienna, Inst Immunol, Ctr Pathophysiol Infectiol & Immunol, A-1090 Vienna, Austria

[2] Med Univ Vienna, Dept Pathophysiol & Allergy Res, Ctr Pathophysiol Infectiol & Immunol, A-1090 Vienna, Austria

[3] Christian Doppler Lab Immunomodulat, Vienna, Austria

关键词: Immune regulation;    regulatory T cells;    allergen-specific T-cell receptor;    FOXP3;    type I allergy;    birch pollen;    Bet v 1;   

DOI  :  10.1016/j.jaci.2010.10.023

来源: Elsevier

【 摘 要 】

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) alpha beta-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 alpha beta-chains. Methods: cDNAs encoding the a and beta-chains of a Bet v 1(142-153)-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. (J Allergy Clin Immunol 2011;127:238-45.)

【 授权许可】

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