J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/03/817/08 $2.00
Volume 185, Number 5, March 3, 1997 817-824

Regulation of the Interleukin (IL)-12R 2 Subunit Expression in Developing T Helper 1 (Th1) and Th2 Cells

By Susanne J. Szabo,^* Anand S. Dighe,^* Ueli Gubler, and Kenneth M. Murphy^*

From the ^* Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110; and the  Department of Inflammation/Autoimmune Diseases Hoffmann La-Roche Inc., Nutley, New Jersey 07110

The developmental commitment to a T helper 1 (Th1)- or Th2-type response can significantly influence host immunity to pathogens. Extinction of the IL-12 signaling pathway during early Th2 development provides a mechanism that allows stable phenotype commitment. In this report we demonstrate that extinction of IL-12 signaling in early Th2 cells results from a selective loss of IL-12 receptor (IL-12R) 2 subunit expression. To determine the basis for this selective loss, we examined IL-12R 2 subunit expression during Th cell development in response to T cell treatment with different cytokines. IL-12R 2 is not expressed by naive resting CD4⁺ T cells, but is induced upon antigen activation through the T cell receptor. Importantly, IL-4 and IFN- were found to significantly modify IL-12 receptor 2 expression after T cell activation. IL-4 inhibited IL-12R 2 expression leading to the loss of IL-12 signaling, providing an important point of regulation to promote commitment to the Th2 pathway. IFN- treatment of early developing Th2 cells maintained IL-12R 2 expression and restored the ability of these cells to functionally respond to IL-12, but did not directly inhibit IL-4 or induce IFN- production. Thus, IFN- may prevent early Th cells from premature commitment to the Th2 pathway. Controlling the expression of the IL-12R 2 subunit could be an important therapeutic target for the redirection of ongoing Th cell responses.

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• Nawijn, M. C., Dingjan, G. M., Ferreira, R., Lambrecht, B. N., Karis, A., Grosveld, F., Savelkoul, H., Hendriks, R. W. (2001). Enforced Expression of GATA-3 in Transgenic Mice Inhibits Th1 Differentiation and Induces the Formation of a T1/ST2-Expressing Th2-Committed T Cell Compartment In Vivo. J. Immunol. 167: 724-732 [Abstract] [Full Text]  
• Cottrez, F., Groux, H. (2001). Regulation of TGF-{{beta}} Response During T Cell Activation Is Modulated by IL-10. J. Immunol. 167: 773-778 [Abstract] [Full Text]  
• Kim, J., Uyemura, K., Van Dyke, M. K., Legaspi, A. J., Rea, T. H., Shuai, K., Modlin, R. L. (2001). A Role for IL-12 Receptor Expression and Signal Transduction in Host Defense in Leprosy. J. Immunol. 167: 779-786 [Abstract] [Full Text]  
• Nutku, E., Zhuang, Q., Soussi-Gounni, A., Aris, F., Mazer, B. D., Hamid, Q. (2001). Functional Expression of IL-12 Receptor by Human Eosinophils: IL-12 Promotes Eosinophil Apoptosis. J. Immunol. 167: 1039-1046 [Abstract] [Full Text]  
• Lieberson, R., Mowen, K. A., McBride, K. D., Leautaud, V., Zhang, X., Suh, W.-K., Wu, L., Glimcher, L. H. (2001). Tumor Necrosis Factor Receptor-associated Factor (TRAF)2 Represses the T Helper Cell Type 2 Response through Interaction with NFAT-interacting Protein (NIP45). JEM 194: 89-98 [Abstract] [Full Text]  
• von der Weid, T., Bulliard, C., Schiffrin, E. J. (2001). Induction by a Lactic Acid Bacterium of a Population of CD4+ T Cells with Low Proliferative Capacity That Produce Transforming Growth Factor {beta} and Interleukin-10. CVI 8: 695-701 [Abstract] [Full Text]  
• Gorbachev, A. V., DiIulio, N. A., Fairchild, R. L. (2001). IL-12 Augments CD8+ T Cell Development for Contact Hypersensitivity Responses and Circumvents Anti-CD154 Antibody-Mediated Inhibition. J. Immunol. 167: 156-162 [Abstract] [Full Text]  
• Grohmann, U., Belladonna, M. L., Vacca, C., Bianchi, R., Fallarino, F., Orabona, C., Fioretti, M. C., Puccetti, P. (2001). Positive Regulatory Role of IL-12 in Macrophages and Modulation by IFN-{{gamma}}. J. Immunol. 167: 221-227 [Abstract] [Full Text]  
• Nishikomori, R., Gurunathan, S., Nishikomori, K., Strober, W. (2001). BALB/c Mice Bearing a Transgenic IL-12 Receptor {{beta}}2 Gene Exhibit a Nonhealing Phenotype to Leishmania major Infection Despite Intact IL-12 Signaling. J. Immunol. 166: 6776-6783 [Abstract] [Full Text]  
• Peng, Y., Falck-Pedersen, E., Elkon, K. B. (2001). Variation in Adenovirus Transgene Expression between BALB/c and C57BL/6 Mice Is Associated with Differences in Interleukin-12 and Gamma Interferon Production and NK Cell Activation. J. Virol. 75: 4540-4550 [Abstract] [Full Text]  
• Kieper, W. C., Prlic, M., Schmidt, C. S., Mescher, M. F., Jameson, S. C. (2001). IL-12 Enhances CD8 T Cell Homeostatic Expansion. J. Immunol. 166: 5515-5521 [Abstract] [Full Text]  
• Ortmann, R., Smeltz, R., Yap, G., Sher, A., Shevach, E. M. (2001). A Heritable Defect in IL-12 Signaling in B10.Q/J Mice. I. In Vitro Analysis. J. Immunol. 166: 5712-5719 [Abstract] [Full Text]  
• Sakai, T., Matsuoka, M., Aoki, M., Nosaka, K., Mitsuya, H. (2001). Missense mutation of the interleukin-12 receptor {beta}1 chain-encoding gene is associated with impaired immunity against Mycobacterium avium complex infection. Blood 97: 2688-2694 [Abstract] [Full Text]  
• Ranganath, S., Murphy, K. M. (2001). Structure and Specificity of GATA Proteins in Th2 Development. Mol. Cell. Biol. 21: 2716-2725 [Abstract] [Full Text]  
• Araujo, M. I., Bliss, S. K., Suzuki, Y., Alcaraz, A., Denkers, E. Y., Pearce, E. J. (2001). Interleukin-12 Promotes Pathologic Liver Changes and Death in Mice Coinfected with Schistosoma mansoni and Toxoplasma gondii. Infect. Immun. 69: 1454-1462 [Abstract] [Full Text]  
• Sullivan, T. J., Letterio, J. J., van Elsas, A., Mamura, M., van Amelsfort, J., Sharpe, S., Metzler, B., Chambers, C. A., Allison, J. P. (2001). Lack of a role for transforming growth factor-beta in cytotoxic T lymphocyte antigen-4-mediated inhibition of T cell activation. Proc. Natl. Acad. Sci. USA 10.1073/pnas.051632398v1 [Abstract] [Full Text]  

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