The Journal of Experimental Medicine
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Published online 1 June 2004 doi:10.1084/jem.20032058
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 11, 1567-1575
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Immune Responses in Healthy and Allergic Individuals Are Characterized by a Fine Balance between Allergen-specific T Regulatory 1 and T Helper 2 Cells

Mübeccel Akdis1, Johan Verhagen1, Alison Taylor1, Fariba Karamloo1, Christian Karagiannidis1, Reto Crameri1, Sarah Thunberg1,2, Günnur Deniz1,3, Rudolf Valenta4, Helmut Fiebig5, Christian Kegel6, Rainer Disch6, Carsten B. Schmidt-Weber1, Kurt Blaser1, and Cezmi A. Akdis1

1 Swiss Institute of Allergy and Asthma Research, CH-7270 Davos, Switzerland
2 Clinical Immunology and Allergy, Karolinska Hospital, 171 76, Stockholm, Sweden
3 Institute for Experimental Medical Research, Istanbul University, 34280 Istanbul, Turkey
4 Department of Pathophysiology, University of Vienna, Medical School, A-1090 Vienna, Austria
5 Allergopharma Joachim Ganzer KG, D-21462 Reinbek, Germany
6 Clinic for Dermatology and Allergy, CH-7270 Davos, Switzerland

Address correspondence to Mübeccel Akdis, Swiss Institute of Allergy and Asthma Research, Obere Strasse 22, CH-7270 Davos, Switzerland. Phone: 41-81-4100848; Fax: 41-81-4100840; email: akdism{at}siaf.unizh.ch

The mechanisms by which immune responses to nonpathogenic environmental antigens lead to either allergy or nonharmful immunity are unknown. Single allergen-specific T cells constitute a very small fraction of the whole CD4+ T cell repertoire and can be isolated from the peripheral blood of humans according to their cytokine profile. Freshly purified interferon-{gamma}–, interleukin (IL)-4–, and IL-10–producing allergen-specific CD4+ T cells display characteristics of T helper cell (Th)1-, Th2-, and T regulatory (Tr)1–like cells, respectively. Tr1 cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals; in contrast, there is a high frequency of allergen-specific IL-4–secreting T cells in allergic individuals. Tr1 cells use multiple suppressive mechanisms, IL-10 and TGF-ß as secreted cytokines, and cytotoxic T lymphocyte antigen 4 and programmed death 1 as surface molecules. Healthy and allergic individuals exhibit all three allergen-specific subsets in different proportions, indicating that a change in the dominant subset may lead to allergy development or recovery. Accordingly, blocking the suppressor activity of Tr1 cells or increasing Th2 cell frequency enhances allergen-specific Th2 cell activation ex vivo. These results indicate that the balance between allergen-specific Tr1 cells and Th2 cells may be decisive in the development of allergy.

Key Words: peripheral tolerance • allergens • suppression • interleukins • immune regulation

The online version of this article contains supplemental material.

Abbreviations used in this paper: CTLA-4, CTL antigen 4; EF-1{alpha}, elongation factor-1{alpha}; L, ligand; PD-1, programmed death 1; PPD, purified protein derivative of Mycobacterium bovis; Tr, T regulatory.


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