Journal of Experimental Medicine, Vol 182, 1579-1584, Copyright © 1995 by Rockefeller University Press

ARTICLES

The effect of antigen dose on CD4+ T helper cell phenotype development in a T cell receptor-alpha beta-transgenic model

NA Hosken, K Shibuya, AW Heath, KM Murphy and A O'Garra
Department of Immunology, DNAX Research Institute, Palo Alto, California 94304, USA.

The dose of foreign antigen can influence whether a cell-mediated or humoral class of immune response is elicited, and this may be largely accounted for by the development of CD4+ T helper cells (Th) producing distinct sets of cytokines. The ability of antigen dose to direct the development of a Th1 or Th2 phenotype from naive CD4+ T cells, however, has not been demonstrated. In this report, we show that the antigen dose used in primary cultures could directly affect Th phenotype development from naive DO11.10 TCR-alpha beta-transgenic CD4+ T cells when dendritic cells or activated B cells were used as the antigen- presenting cells. Consistent with our previous findings, midrange peptide doses (0.3-0.6 microM) directed the development of Th0/Th1-like cells, which produced moderate amounts of interferon gamma (IFN-gamma). As the peptide dose was increased, development of Th1-like cells producing increased amounts of IFN-gamma was initially observed. At very high (> 10 microM) and very low (< 0.05 microM) doses of antigenic peptide, however, a dramatic switch to development of Th2-like cells that produced increasing amounts of interleukin 4 (IL-4) and diminishing levels of IFN-gamma was observed. This was true even when highly purified naive, high buoyant density CD4+ LECAM-1hi T cells were used, ruling out a possible contribution from contaminating "memory" phenotype CD4+ T cells. Neutralizing anti-IL-4 antibodies completely inhibited the development of this Th2-like phenotype at both high and low antigen doses, demonstrating a requirement for endogenous IL-4. Our findings suggest that the antigen dose may affect the levels of endogenous cytokines such as IL-4 in primary cultures, resulting in the development of distinct Th cell phenotypes.
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• Jonuleit, H., Schmitt, E., Schuler, G., Knop, J., Enk, A. H. (2000). Induction of Interleukin 10-producing, Nonproliferating CD4+ T Cells with Regulatory Properties by Repetitive Stimulation with Allogeneic Immature Human Dendritic Cells. JEM 192: 1213-1222 [Abstract] [Full Text]  
• Noben-Trauth, N., Hu-Li, J., Paul, W. E. (2000). Conventional, Naive CD4+ T Cells Provide an Initial Source of IL-4 During Th2 Differentiation. J. Immunol. 165: 3620-3625 [Abstract] [Full Text]  
• Zhang, F., Rincon, M., Flavell, R. A., Aune, T. M. (2000). Defective Th Function Induced by a Dominant-Negative cAMP Response Element Binding Protein Mutation Is Reversed by Bcl-2. J. Immunol. 165: 1762-1770 [Abstract] [Full Text]  
• Whelan, M., Harnett, M. M., Houston, K. M., Patel, V., Harnett, W., Rigley, K. P. (2000). A Filarial Nematode-Secreted Product Signals Dendritic Cells to Acquire a Phenotype That Drives Development of Th2 Cells. J. Immunol. 164: 6453-6460 [Abstract] [Full Text]  
• Terheyden, P., Straten, P. t., Brocker, E.-B., Kampgen, E., Becker, J. C. (2000). CD40-Ligated Dendritic Cells Effectively Expand Melanoma-Specific CD8+ CTLs and CD4+ IFN-{gamma}-Producing T Cells from Tumor-Infiltrating Lymphocytes. J. Immunol. 164: 6633-6639 [Abstract] [Full Text]  
• Ma, H., Kapp, J. A. (2000). Antigenic Epitopes Regulate the Phenotype of CD8+ CTL Primed by Exogenous Antigens. J. Immunol. 164: 5698-5703 [Abstract] [Full Text]  
• Heeger, P. S., Forsthuber, T., Shive, C., Biekert, E., Genain, C., Hofstetter, H. H., Karulin, A., Lehmann, P. V. (2000). Revisiting Tolerance Induced by Autoantigen in Incomplete Freund's Adjuvant. J. Immunol. 164: 5771-5781 [Abstract] [Full Text]  
• Yamashita, M., Katsumata, M., Iwashima, M., Kimura, M., Shimizu, C., Kamata, T., Shin, T., Seki, N., Suzuki, S., Taniguchi, M., Nakayama, T. (2000). T Cell Receptor-induced Calcineurin Activation Regulates T Helper Type 2 Cell Development by Modifying the Interleukin 4 Receptor Signaling Complex. JEM 191: 1869-1880 [Abstract] [Full Text]  
• Robertson, J. M., Jensen, P. E., Evavold, B. D. (2000). DO11.10 and OT-II T Cells Recognize a C-Terminal Ovalbumin 323-339 Epitope. J. Immunol. 164: 4706-4712 [Abstract] [Full Text]  
• Nakata, Y., Uzawa, A., Suzuki, G. (2000). Control of CD4 T cell fate by antigen re-stimulation with or without CTLA-4 engagement 24 h after priming. Int Immunol 12: 459-466 [Abstract] [Full Text]  

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