J. Exp. Med., Volume 188, Number 6, September 21, 1998 1191-1196

A Signal Transducer and Activator of  Transcription (Stat)4-independent Pathway for the Development of  T Helper Type 1 Cells

By Mark H. Kaplan,^* Andrea L. Wurster,^* and Michael J. Grusby^*

From the ^* Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115; and the  Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115

The differentiation of T helper (Th) cells is regulated by members of the signal transducer and activator of transcription (STAT) family of signaling molecules. We have generated mice lacking both Stat4 and Stat6 to examine the ability of Th cells to develop in the absence of these two transcription factors. Stat4, Stat6^/ lymphocytes fail to differentiate into interleukin (IL)-4-secreting Th2 cells. However, in contrast to Stat4^/ lymphocytes, T cells from Stat4, Stat6^/ mice produce significant amounts of interferon (IFN)- when activated in vitro. Although Stat4, Stat6^/ lymphocytes produce less IFN- than IL-12-stimulated control lymphocytes, equivalent numbers of IFN--secreting cells can be generated from cultures of Stat4, Stat6^/ lymphocytes activated under neutral conditions and control lymphocytes activated under Th1 cell-promoting conditions. Moreover, Stat4, Stat6^/ mice are able to mount an in vivo Th1 cell-mediated delayed-type hypersensitivity response. These results support a model of Th cell differentiation in which the generation of Th2 cells requires Stat6, whereas a Stat4-independent pathway exists for the development of Th1 cells.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Johnson, L. M., Scott, P. (2007). STAT1 Expression in Dendritic Cells, but Not T Cells, Is Required for Immunity to Leishmania major. J. Immunol. 178: 7259-7266 [Abstract] [Full Text]  
• Pellicano, A., Sebkova, L., Monteleone, G., Guarnieri, G., Imeneo, M., Pallone, F., Luzza, F. (2007). Interleukin-12 Drives the Th1 Signaling Pathway in Helicobacter pylori-Infected Human Gastric Mucosa. Infect. Immun. 75: 1738-1744 [Abstract] [Full Text]  
• Tato, C. M., Mason, N., Artis, D., Shapira, S., Caamano, J. C., Bream, J. H., Liou, H.-C., Hunter, C. A. (2006). Opposing roles of NF-{kappa}B family members in the regulation of NK cell proliferation and production of IFN-{gamma}. Int Immunol 18: 505-513 [Abstract] [Full Text]  
• Usui, T., Preiss, J. C., Kanno, Y., Yao, Z. J., Bream, J. H., O'Shea, J. J., Strober, W. (2006). T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. J. Exp. Med. 203: 755-766 [Abstract] [Full Text]  
• Boyton, R. J., Davies, S., Marden, C., Fantino, C., Reynolds, C., Portugal, K., Dewchand, H., Altmann, D. M. (2005). Stat4-null non-obese diabetic mice: protection from diabetes and experimental allergic encephalomyelitis, but with concomitant epitope spread. Int Immunol 17: 1157-1165 [Abstract] [Full Text]  
• Feng, C. G., Jankovic, D., Kullberg, M., Cheever, A., Scanga, C. A., Hieny, S., Caspar, P., Yap, G. S., Sher, A. (2005). Maintenance of Pulmonary Th1 Effector Function in Chronic Tuberculosis Requires Persistent IL-12 Production. J. Immunol. 174: 4185-4192 [Abstract] [Full Text]  
• Sanchez-Guajardo, V., Borghans, J. A. M., Marquez, M.-E., Garcia, S., Freitas, A. A. (2005). Different Competitive Capacities of Stat4- and Stat6-Deficient CD4+ T Cells during Lymphophenia-Driven Proliferation. J. Immunol. 174: 1178-1187 [Abstract] [Full Text]  
• Kataoka, T. R., Komazawa, N., Morii, E., Oboki, K., Nakano, T. (2005). Involvement of connective tissue-type mast cells in Th1 immune responses via Stat4 expression. Blood 105: 1016-1020 [Abstract] [Full Text]  
• Deng, J. C., Zeng, X., Newstead, M., Moore, T. A., Tsai, W. C., Thannickal, V. J., Standiford, T. J. (2004). STAT4 Is a Critical Mediator of Early Innate Immune Responses against Pulmonary Klebsiella Infection. J. Immunol. 173: 4075-4083 [Abstract] [Full Text]  
• Jankovic, D., Kullberg, M. C., Caspar, P., Sher, A. (2004). Parasite-Induced Th2 Polarization Is Associated with Down-Regulated Dendritic Cell Responsiveness to Th1 Stimuli and a Transient Delay in T Lymphocyte Cycling. J. Immunol. 173: 2419-2427 [Abstract] [Full Text]  
• Yu, C.-R., Mahdi, R. M., Ebong, S., Vistica, B. P., Chen, J., Guo, Y., Gery, I., Egwuagu, C. E. (2004). Cell Proliferation and STAT6 Pathways Are Negatively Regulated in T Cells by STAT1 and Suppressors of Cytokine Signaling. J. Immunol. 173: 737-746 [Abstract] [Full Text]  
• Lund, R. J., Chen, Z., Scheinin, J., Lahesmaa, R. (2004). Early Target Genes of IL-12 and STAT4 Signaling in Th Cells. J. Immunol. 172: 6775-6782 [Abstract] [Full Text]  
• Chitnis, T., Salama, A. D., Grusby, M. J., Sayegh, M. H., Khoury, S. J. (2004). Defining Th1 and Th2 Immune Responses in a Reciprocal Cytokine Environment In Vivo. J. Immunol. 172: 4260-4265 [Abstract] [Full Text]  
• Park, W.-R., Nakahira, M., Sugimoto, N., Bian, Y., Yashiro-Ohtani, Y., Zhou, X.-Y., Yang, Y.-F., Hamaoka, T., Fujiwara, H. (2004). A mechanism underlying STAT4-mediated up-regulation of IFN-{gamma} induction inTCR-triggered T cells. Int Immunol 16: 295-302 [Abstract] [Full Text]  
• Wang, W., Ostlie, N. S., Conti-Fine, B. M., Milani, M. (2004). The Susceptibility to Experimental Myasthenia Gravis of STAT6-/- and STAT4-/- BALB/c Mice Suggests a Pathogenic Role of Th1 Cells. J. Immunol. 172: 97-103 [Abstract] [Full Text]  
• Zheng, W.-p., Zhao, Q., Zhao, X., Li, B., Hubank, M., Schatz, D. G., Flavell, R. A. (2004). Up-Regulation of Hlx in Immature Th Cells Induces IFN-{gamma} Expression. J. Immunol. 172: 114-122 [Abstract] [Full Text]  
• Jacob, C. O., Zang, S., Li, L., Ciobanu, V., Quismorio, F., Mizutani, A., Satoh, M., Koss, M. (2003). Pivotal Role of Stat4 and Stat6 in the Pathogenesis of the Lupus-Like Disease in the New Zealand Mixed 2328 Mice. J. Immunol. 171: 1564-1571 [Abstract] [Full Text]  
• Bot, A., Rodrigo, E., Wolfe, T., Bot, S., Von Herrath, M. G. (2003). Infection-Triggered Regulatory Mechanisms Override the Role of STAT 4 in Control of the Immune Response to Influenza Virus Antigens. J. Virol. 77: 5794-5800 [Abstract] [Full Text]  
• Brown, G. R., Lee, E. L., Thiele, D. L. (2003). TNF Enhances CD4+ T Cell Alloproliferation, IFN-{gamma} Responses, and Intestinal Graft-Versus-Host Disease by IL-12-Independent Mechanisms. J. Immunol. 170: 5082-5088 [Abstract] [Full Text]  
• Raman, K., Kaplan, M. H., Hogaboam, C. M., Berlin, A., Lukacs, N. W. (2003). STAT4 Signal Pathways Regulate Inflammation and Airway Physiology Changes in Allergic Airway Inflammation Locally Via Alteration of Chemokines. J. Immunol. 170: 3859-3865 [Abstract] [Full Text]  
• Zhou, W., Zhang, F., Aune, T. M. (2003). Either IL-2 or IL-12 Is Sufficient to Direct Th1 Differentiation by Nonobese Diabetic T Cells. J. Immunol. 170: 735-740 [Abstract] [Full Text]  
• Cleary, A. M., Tu, W., Enright, A., Giffon, T., Dewaal-Malefyt, R., Gutierrez, K., Lewis, D. B. (2003). Impaired Accumulation and Function of Memory CD4 T Cells in Human IL-12 Receptor {beta}1 Deficiency. J. Immunol. 170: 597-603 [Abstract] [Full Text]  
• Scott, M. J., Godshall, C. J., Cheadle, W. G. (2002). Jaks, STATs, Cytokines, and Sepsis. CVI 9: 1153-1159 [Full Text]  
• Chang, H.-C., Zhang, S., Kaplan, M. H. (2002). Neonatal Tolerance in the Absence of Stat4- and Stat6- Dependent Th Cell Differentiation. J. Immunol. 169: 4124-4128 [Abstract] [Full Text]  
• Morinobu, A., Gadina, M., Strober, W., Visconti, R., Fornace, A., Montagna, C., Feldman, G. M., Nishikomori, R., O'Shea, J. J. (2002). STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Proc. Natl. Acad. Sci. USA 99: 12281-12286 [Abstract] [Full Text]  
• Finnegan, A., Grusby, M. J., Kaplan, C. D., O'Neill, S. K., Eibel, H., Koreny, T., Czipri, M., Mikecz, K., Zhang, J. (2002). IL-4 and IL-12 Regulate Proteoglycan-Induced Arthritis Through Stat-Dependent Mechanisms. J. Immunol. 169: 3345-3352 [Abstract] [Full Text]  
• Smeltz, R. B., Chen, J., Ehrhardt, R., Shevach, E. M. (2002). Role of IFN-{gamma} in Th1 Differentiation: IFN-{gamma} Regulates IL-18R{alpha} Expression by Preventing the Negative Effects of IL-4 and by Inducing/Maintaining IL-12 Receptor {beta}2 Expression. J. Immunol. 168: 6165-6172 [Abstract] [Full Text]  
• Natarajan, C., Bright, J. J. (2002). Curcumin Inhibits Experimental Allergic Encephalomyelitis by Blocking IL-12 Signaling Through Janus Kinase-STAT Pathway in T Lymphocytes. J. Immunol. 168: 6506-6513 [Abstract] [Full Text]  
• Ise, W., Totsuka, M., Sogawa, Y., Ametani, A., Hachimura, S., Sato, T., Kumagai, Y., Habu, S., Kaminogawa, S. (2002). Naive CD4+ T Cells Exhibit Distinct Expression Patterns of Cytokines and Cell Surface Molecules on Their Primary Responses to Varying Doses of Antigen. J. Immunol. 168: 3242-3250 [Abstract] [Full Text]  
• Bajenoff, M., Wurtz, O., Guerder, S. (2002). Repeated Antigen Exposure Is Necessary for the Differentiation, But Not the Initial Proliferation, of Naive CD4+ T Cells. J. Immunol. 168: 1723-1729 [Abstract] [Full Text]  
• Wurster, A. L., Withers, D. J., Uchida, T., White, M. F., Grusby, M. J. (2002). Stat6 and IRS-2 Cooperate in Interleukin 4 (IL-4)-Induced Proliferation and Differentiation but Are Dispensable for IL-4-Dependent Rescue from Apoptosis. Mol. Cell. Biol. 22: 117-126 [Abstract] [Full Text]  
• Lim, Y.-C., Xie, H., Come, C. E., Alexander, S. I., Grusby, M. J., Lichtman, A. H., Luscinskas, F. W. (2001). IL-12, STAT4-Dependent Up-Regulation of CD4+ T Cell Core 2 {beta}-1,6-n-Acetylglucosaminyltransferase, an Enzyme Essential for Biosynthesis of P-Selectin Ligands. J. Immunol. 167: 4476-4484 [Abstract] [Full Text]  
• Kiani, A., Garcia-Cozar, F. J., Habermann, I., Laforsch, S., Aebischer, T., Ehninger, G., Rao, A. (2001). Regulation of interferon-{gamma} gene expression by nuclear factor of activated T cells. Blood 98: 1480-1488 [Abstract] [Full Text]  
• Mullen, A. C., High, F. A., Hutchins, A. S., Lee, H. W., Villarino, A. V., Livingston, D. M., Kung, A. L., Cereb, N., Yao, T.-P., Yang, S. Y., Reiner, S. L. (2001). Role of T-bet in Commitment of TH1 Cells Before IL-12-Dependent Selection. Science 292: 1907-1910 [Abstract] [Full Text]  
• Huber, S. A., Sakkinen, P., David, C., Newell, M. K., Tracy, R. P. (2001). T Helper-Cell Phenotype Regulates Atherosclerosis in Mice Under Conditions of Mild Hypercholesterolemia. Circulation 103: 2610-2616 [Abstract] [Full Text]  
• Schindler, H., Lutz, M. B., Rollinghoff, M., Bogdan, C. (2001). The Production of IFN-{{gamma}} by IL-12/IL-18-Activated Macrophages Requires STAT4 Signaling and Is Inhibited by IL-4. J. Immunol. 166: 3075-3082 [Abstract] [Full Text]  
• Cai, G., Kastelein, R., Hunter, C. A. (2000). Interleukin-18 (IL-18) Enhances Innate IL-12-Mediated Resistance to Toxoplasma gondii. Infect. Immun. 68: 6932-6938 [Abstract] [Full Text]  
• Ostrand-Rosenberg, S., Grusby, M. J., Clements, V. K. (2000). Cutting Edge: STAT6-Deficient Mice Have Enhanced Tumor Immunity to Primary and Metastatic Mammary Carcinoma. J. Immunol. 165: 6015-6019 [Abstract] [Full Text]  
• Zhou, P., Szot, G. L., Guo, Z., Kim, O., He, G., Wang, J., Grusby, M. J., Newell, K. A., Thistlethwaite, J. R., Bluestone, J. A., Alegre, M.-L. (2000). Role of STAT4 and STAT6 Signaling in Allograft Rejection and CTLA4-Ig-Mediated Tolerance. J. Immunol. 165: 5580-5587 [Abstract] [Full Text]  
• Lee, C.-K., Rao, D. T., Gertner, R., Gimeno, R., Frey, A. B., Levy, D. E. (2000). Distinct Requirements for IFNs and STAT1 in NK Cell Function. J. Immunol. 165: 3571-3577 [Abstract] [Full Text]  
• Cai, G., Radzanowski, T., Villegas, E. N., Kastelein, R., Hunter, C. A. (2000). Identification of STAT4-Dependent and Independent Mechanisms of Resistance to Toxoplasma gondii. J. Immunol. 165: 2619-2627 [Abstract] [Full Text]  
• Zhang, S., Kaplan, M. H. (2000). The p38 Mitogen-Activated Protein Kinase Is Required for IL-12-Induced IFN-{gamma} Expression. J. Immunol. 165: 1374-1380 [Abstract] [Full Text]  
• Lohoff, M., Duncan, G. S., Ferrick, D., Mittrucker, H.-W., Bischof, S., Prechtl, S., Rollinghoff, M., Schmitt, E., Pahl, A., Mak, T. W. (2000). Deficiency in the Transcription Factor Interferon Regulatory Factor (IRF)-2 Leads to Severely Compromised Development of Natural Killer and T Helper Type 1 Cells. J. Exp. Med. 192: 325-336 [Abstract] [Full Text]  
• Glimcher, L. H., Murphy, K. M. (2000). Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev. 14: 1693-1711 [Full Text]  
• Zhang, S., Lukacs, N. W., Lawless, V. A., Kunkel, S. L., Kaplan, M. H. (2000). Cutting Edge: Differential Expression of Chemokines in Th1 and Th2 Cells Is Dependent on Stat6 But Not Stat4. J. Immunol. 165: 10-14 [Abstract] [Full Text]  
• Jankovic, D., Kullberg, M. C., Noben-Trauth, N., Caspar, P., Paul, W. E., Sher, A. (2000). Single Cell Analysis Reveals That IL-4 Receptor/Stat6 Signaling Is Not Required for the In Vivo or In Vitro Development of CD4+ Lymphocytes with a Th2 Cytokine Profile. J. Immunol. 164: 3047-3055 [Abstract] [Full Text]  
• Ward, A. C., Touw, I., Yoshimura, A. (2000). The Jak-Stat pathway in normal and perturbed hematopoiesis. Blood 95: 19-29 [Full Text]  
• Kaplan, M. H., Wurster, A. L., Smiley, S. T., Grusby3, M. J. (1999). Stat6-Dependent and -Independent Pathways for IL-4 Production. J. Immunol. 163: 6536-6540 [Abstract] [Full Text]  
• Carter, L. L., Murphy, K. M. (1999). Lineage-specific Requirement for Signal Transducer and Activator of  Transcription (Stat)4 in Interferon gamma  Production from CD4+ Versus CD8+ T Cells. J. Exp. Med. 189: 1355-1360 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS