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Xiaohong Zhang^*, Thomas Brunner, Laura Carter^*, Richard W. Dutton^*, Paul Rogers^*, Linda Bradley^*, Takaaki Sato, John C. Reed, Douglas Green, and Susan L. Swain^*,||

From the ^* University of California, San Diego, La Jolla, California 92093; La Jolla Institute of Allergy and Immunology, San Diego, California 92121; The Burnham Institute, La Jolla, California 92037; and ^|| Trudeau Institute, Saranac Lake, New York 12983

T helper cell (Th) 1, but not Th2, effectors undergo rapid Fas/Fas ligand (FasL)-mediated, activation-induced cell death upon restimulation with antigen. Unequal apoptosis is also observed without restimulation, after a longer lag period. Both effectors undergo delayed apoptosis induced by a non–Fas-mediated pathway. When Th1 and Th2 effectors are co-cultured, Th2 effectors survive preferentially, suggesting the responsible factor(s) is intrinsic to each population. Both Th1 and Th2 effectors express Fas and FasL, but only Th2 effectors express high levels of FAP-1, a Fas-associated phosphatase that may act to inhibit Fas signaling. The rapid death of Th1 effectors leading to selective Th2 survival provides a novel mechanism for differential regulation of the two subsets.

The authors are thankful to S. Nagata and P. Golstein for providing valuable reagents.

This research was supported by National Institutes of Health grants AI37935 and AI26887 to S.L. Swain, GM52735 to D.R. Green, CA72994 and ACS IM414 to J.C. Reed, and a fellowship from the U.S. Army Breast Cancer Program to T. Sato. T. Brunner is a fellow of the Swiss Society for Med. Biol. Fellowships.

¹Abbreviations used in this paper: AICD, activation-induced cell death; CFSE, 5- (and 6-) carboxyfluorescein diacetate succinimidyl ester; FasL, Fas ligand; ICAM, intracellular adhesion molecule; FAP-1, Fas-associated phosphatase 1; FL, fluorescein; mRNA, messenger RNA; PCCF, pigeon cytochrome c fragment 88-104; RPA, RNase protection assay; TdT, terminal deoxynucleotidyl transferase; Tg, transgenic.

X. Zhang and T. Brunner contributed equally to this work.

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• Marchant, A., Amedei, A., Azzurri, A., Vekemans, J., Benagiano, M., Tamburini, C., Lienhardt, C., Corrah, T., McAdam, K. P. W. J., Romagnani, S., D'Elios, M. M., Del Prete, G. (2001). Polarization of PPD-Specific T-Cell Response of Patients with Tuberculosis from Th0 to Th1 Profile after Successful Antimycobacterial Therapy or In Vitro Conditioning with Interferon-{alpha} or Interleukin-12. Am. J. Respir. Cell Mol. Bio. 24: 187-194 [Abstract] [Full Text]  
• Serreze, D. V., Chapman, H. D., Post, C. M., Johnson, E. A., Suarez-Pinzon, W. L., Rabinovitch, A. (2001). Th1 to Th2 Cytokine Shifts in Nonobese Diabetic Mice: Sometimes an Outcome, Rather Than the Cause, of Diabetes Resistance Elicited by Immunostimulation. J. Immunol. 166: 1352-1359 [Abstract] [Full Text]  
• Ungefroren, H., Kruse, M.-L., Trauzold, A., Roeschmann, S., Roeder, C., Arlt, A., Henne-Bruns, D., Kalthoff, H. (2001). FAP-1 in pancreatic cancer cells: functional and mechanistic studies on its inhibitory role in CD95-mediated apoptosis. J. Cell Sci. 114: 2735-2746 [Abstract] [Full Text]  
• Kjærgaard, J., Tanaka, J., Kim, J. A., Rothchild, K., Weinberg, A., Shu, S. (2000). Therapeutic Efficacy of OX-40 Receptor Antibody Depends on Tumor Immunogenicity and Anatomic Site of Tumor Growth. Cancer Res. 60: 5514-5521 [Abstract] [Full Text]  
• Chung, Y.-H., Jun, H. S., Son, M., Bao, M., Bae, H. Y., Kang, Y., Yoon, J.-W. (2000). Cellular and Molecular Mechanism for Kilham Rat Virus-Induced Autoimmune Diabetes in DR-BB Rats. J. Immunol. 165: 2866-2876 [Abstract] [Full Text]  
• Steigerwald-Mullen, P., Kurilla, M. G., Braciale, T. J. (2000). Type 2 Cytokines Predominate in the Human CD4+ T-Lymphocyte Response to Epstein-Barr Virus Nuclear Antigen 1. J. Virol. 74: 6748-6759 [Abstract] [Full Text]  
• Park, A. Y., Hondowicz, B. D., Scott, P. (2000). IL-12 Is Required to Maintain a Th1 Response During Leishmania major Infection. J. Immunol. 165: 896-902 [Abstract] [Full Text]  
• Varga, S. M., Welsh, R. M. (2000). High Frequency of Virus-Specific Interleukin-2-Producing CD4+ T Cells and Th1 Dominance during Lymphocytic Choriomeningitis Virus Infection. J. Virol. 74: 4429-4432 [Abstract] [Full Text]  
• Norian, L. A., Latinis, K. M., Eliason, S. L., Lyson, K., Yang, C., Ratliff, T., Koretzky, G. A. (2000). The Regulation of CD95 (Fas) Ligand Expression in Primary T Cells: Induction of Promoter Activation in CD95LP-Luc Transgenic Mice. J. Immunol. 164: 4471-4480 [Abstract] [Full Text]  
• Suzuki, I., Fink, P. J. (2000). The dual functions of Fas ligand in the regulation of peripheral CD8+ and CD4+ T cells. Proc. Natl. Acad. Sci. USA 97: 1707-1712 [Abstract] [Full Text]  
• Batteux, F., Lores, P., Bucchini, D., Chiocchia, G. (2000). Transgenic Expression of Fas Ligand on Thyroid Follicular Cells Prevents Autoimmune Thyroiditis. J. Immunol. 164: 1681-1688 [Abstract] [Full Text]  
• Weinberg, A. D., Rivera, M.-M., Prell, R., Morris, A., Ramstad, T., Vetto, J. T., Urba, W. J., Alvord, G., Bunce, C., Shields, J. (2000). Engagement of the OX-40 Receptor In Vivo Enhances Antitumor Immunity. J. Immunol. 164: 2160-2169 [Abstract] [Full Text]  
• Vandenbark, A. A., Barnes, D., Finn, T., Bourdette, D. N., Whitham, R., Robey, I., Kaleeba, J., Bebo, B. F. Jr, Miller, S. D., Offner, H., Chou, Y. K. (2000). Differential susceptibility of human Th1 versus T h 2 cells to induction of anergy and apoptosis by ECDI/antigen-coupled antigen-presenting cells. Int Immunol 12: 57-66 [Abstract] [Full Text]  

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