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Epicutaneous Immunization with Protein Antigen in the Presence of TLR4 Ligand Induces TCRβ⁺CD4⁺ T Contrasuppressor Cells That Reverse Skin-Induced Suppression of Th1-Mediated Contact Sensitivity¹

Wodzimierz Ptak^*, Monika Majewska, Krzysztof Bryniarski^*, Maria Ptak^*, Francis M. Lobo, Katarzyna Zajc, Philip W. Askenase and Marian Szczepanik^2,

^* Department of Immunology and Department of Human Developmental Biology, Jagiellonian University College of Medicine, Kraków, Poland; and Section of Allergy and Clinical Immunology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520

Our previous work showed that epicutaneous (EC) immunization of mice with different protein Ags applied on the skin in the form of a patch induces a state of subsequent Ag-nonspecific unresponsiveness due to suppressor CD4⁺8⁺ T cells (Ts) that inhibit Th1-mediated contact sensitivity (CS) reactions via released TGF-β. In the present work we show that EC immunization with Ag together with the TLR4 ligand LPS induced cells that could prevent suppression by the Ag-nonspecific Ts. These up-regulatory cells, called contrasuppressor T cells (Tcs), belong to a population of Ag-specific TCRβ CD4⁺ lymphocytes and are different from Th1 CD4⁺ cells that mediate the CS reaction. Experiments using knockout mice showed that EC induced contrasuppression is MyD88, INF-, and IL-12 dependent, whereas IL-6 is not involved in this phenomenon. Additional experiments with anti-IFN- mAb showed that IFN- is required for induction of Tcs cells but does not play a crucial role in the effector phase of contrasuppression. Additionally, treatment of CS effector cells with rIL-12 makes them resistant to EC induced suppression without affecting Ts cells, whereas IL-12 neutralization in vitro abrogates contrasuppression. These data show that IL-12 is indeed involved in the effector phase of EC induced contrasuppression and that this cytokine does not act directly on Ts cells. The mechanism of action of Tcs protects Th1 effector cells mediating CS from the nonspecific Ts, leaving suppression to other Ags intact. Ts and Tcs cells do not influence each other and can be induced simultaneously in the same animal.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Polish Committee of Scientific Research Grants 3 PO5B 091 25, 2PO5A 204 29, 2PO5A 157 28, and N N401 3553 33 and by National Institutes of Health Grant AI-59801 (to P.W.A.).

² Address correspondence and reprint requests to Dr. Marian Szczepanik, Department of Human Developmental Biology, Jagiellonian University College of Medicine, Kopernika 7, 31-034 Kraków, Poland. E-mail address: mmszczep{at}cyf-kr.edu.pl or marian_szczepanik{at}yahoo.com

³ Abbreviations used in this paper: EC, epicutaneous; CS, contact sensitivity; LN, lymph node; OX, oxazolone; RC, rabbit complement; TNP, trinitrophenyl; TNP-Cl, TNP chloride; Tcs, T contrasuppressor cell; Ts, T suppressor cell.