© The Rockefeller University Press, 0022-1007/1998/11/1859/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 10, November 16, 1998 1859-1866
c-maf Promotes T Helper Cell Type 2 (Th2) and Attenuates Th1 Differentiation by Both Interleukin 4–dependent and –independent Mechanisms
I-Cheng Ho*,
,
David Lo
, and
Laurie H. Glimcher*,
From the * Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115; the
Department of Immunology and Rheumatology, Harvard Medical School, Boston, Massachusetts 02115; and the
Department of Immunology, Scripps Research Institute, La Jolla, California 92037
The c-maf protooncogene is a T helper cell type 2 (Th2)-specific transcription factor that activates the interleukin (IL)-4 promoter in vitro. Although it has been postulated that c-maf directs the Th2-specific expression of the IL-4 gene in vivo, direct evidence that c-maf functions during the differentiation of normal, primary T cells is lacking. We now demonstrate that overexpression of c-maf in vivo skews the Th immune response along a Th2 pathway, as evidenced by increased production of Th2 cytokines and the IL-4–dependent immunoglobulins, IgG1 and IgE. The overproduction of IgGl and IgE in the CD4 promoter/c-maf transgenic mice was IL-4 dependent since this was not observed in c-maf transgenic mice bred onto an IL-4–deficient background. Ectopic expression of c-maf in mature Th1 cells did not confer on them the ability to produce IL-4, but did decrease the production of IFN-
. The attenuation of Th1 differentiation by c-maf overexpression occurred by a mechanism that was independent of IL-4 and other Th2 cytokines, and could be overcome by IL-12. These studies demonstrate that c-maf promotes Th2 differentiation by IL-4–dependent mechanisms and attenuates Th1 differentiation by Th2 cytokine-independent mechanisms.
Key Words: interleukin 4 T helper cells c-maf transcription factor
Address correspondence to Laurie H. Glimcher, Department of Immunology and Infectious Diseases, Harvard School of Public Health, 651 Huntington Ave., FXB-2, Boston, MA 02115-6017. Phone: 617-432-0622; Fax: 617-432-0084; E-mail: lglimche{at}hsph.harvard.edu
Abbreviations used: NFAT, nuclear factor of activated T cells; RT, reverse transcription.

CiteULike
Complore
Connotea
Del.icio.us
Digg
Facebook
Reddit
Technorati
Twitter What's this?
This article has been cited by other articles:
-
Xu, J., Yang, Y., Qiu, G., Lal, G., Wu, Z., Levy, D. E., Ochando, J. C., Bromberg, J. S., Ding, Y.
(2009). c-Maf Regulates IL-10 Expression during Th17 Polarization. J. Immunol.
182: 6226-6236
[Abstract]
[Full Text]
-
Zhang, G., Rowe, J., Kusel, M., Bosco, A., McKenna, K., de Klerk, N., Sly, P. D., Holt, P. G.
(2009). Interleukin-10/Interleukin-5 Responses at Birth Predict Risk for Respiratory Infections in Children with Atopic Family History. Am. J. Respir. Crit. Care Med.
179: 205-211
[Abstract]
[Full Text]
-
Sasaki, K., Zhao, X., Pardee, A. D., Ueda, R., Fujita, M., Sehra, S., Kaplan, M. H., Kane, L. P., Okada, H., Storkus, W. J.
(2008). Stat6 Signaling Suppresses VLA-4 Expression by CD8+ T Cells and Limits Their Ability to Infiltrate Tumor Lesions In Vivo. J. Immunol.
181: 104-108
[Abstract]
[Full Text]
-
Khaled, W. T., Read, E. K. C., Nicholson, S. E., Baxter, F. O., Brennan, A. J., Came, P. J., Sprigg, N., McKenzie, A. N. J., Watson, C. J.
(2007). The IL-4/IL-13/Stat6 signalling pathway promotes luminal mammary epithelial cell development. Development
134: 2739-2750
[Abstract]
[Full Text]
-
Rodriguez, A., Vigorito, E., Clare, S., Warren, M. V., Couttet, P., Soond, D. R., van Dongen, S., Grocock, R. J., Das, P. P., Miska, E. A., Vetrie, D., Okkenhaug, K., Enright, A. J., Dougan, G., Turner, M., Bradley, A.
(2007). Requirement of bic/microRNA-155 for Normal Immune Function. Science
316: 608-611
[Abstract]
[Full Text]
-
Chen, L., He, W., Kim, S. T., Tao, J., Gao, Y., Chi, H., Intlekofer, A. M., Harvey, B., Reiner, S. L., Yin, Z., Flavell, R. A., Craft, J.
(2007). Epigenetic and Transcriptional Programs Lead to Default IFN-{gamma} Production by {gamma}{delta} T Cells. J. Immunol.
178: 2730-2736
[Abstract]
[Full Text]
-
Ogawa, K., Funaba, M., Chen, Y., Tsujimoto, M.
(2006). Activin A Functions as a Th2 Cytokine in the Promotion of the Alternative Activation of Macrophages. J. Immunol.
177: 6787-6794
[Abstract]
[Full Text]
-
Suto, A., Wurster, A. L., Reiner, S. L., Grusby, M. J.
(2006). IL-21 Inhibits IFN-{gamma} Production in Developing Th1 Cells through the Repression of Eomesodermin Expression. J. Immunol.
177: 3721-3727
[Abstract]
[Full Text]
-
Cannarile, L., Fallarino, F., Agostini, M., Cuzzocrea, S., Mazzon, E., Vacca, C., Genovese, T., Migliorati, G., Ayroldi, E., Riccardi, C.
(2006). Increased GILZ expression in transgenic mice up-regulates Th-2 lymphokines. Blood
107: 1039-1047
[Abstract]
[Full Text]
-
Georas, S. N., Guo, J., De Fanis, U., Casolaro, V.
(2005). T-helper cell type-2 regulation in allergic disease. Eur Respir J
26: 1119-1137
[Abstract]
[Full Text]
-
Tanaka, Y., So, T., Lebedeva, S., Croft, M., Altman, A.
(2005). Impaired IL-4 and c-Maf expression and enhanced Th1-cell development in Vav1-deficient mice. Blood
106: 1286-1295
[Abstract]
[Full Text]
-
Dardalhon, V., Schubart, A. S., Reddy, J., Meyers, J. H., Monney, L., Sabatos, C. A., Ahuja, R., Nguyen, K., Freeman, G. J., Greenfield, E. A., Sobel, R. A., Kuchroo, V. K.
(2005). CD226 Is Specifically Expressed on the Surface of Th1 Cells and Regulates Their Expansion and Effector Functions. J. Immunol.
175: 1558-1565
[Abstract]
[Full Text]
-
Xu, J., Vallejo, A. N., Jiang, Y., Weyand, C. M., Goronzy, J. J.
(2005). Distinct Transcriptional Control Mechanisms of Killer Immunoglobulin-like Receptors in Natural Killer (NK) and in T Cells. J. Biol. Chem.
280: 24277-24285
[Abstract]
[Full Text]
-
Yang, Y., Ochando, J., Yopp, A., Bromberg, J. S., Ding, Y.
(2005). IL-6 Plays a Unique Role in Initiating c-Maf Expression during Early Stage of CD4 T Cell Activation. J. Immunol.
174: 2720-2729
[Abstract]
[Full Text]
-
Mehta, D. S., Wurster, A. L., Weinmann, A. S., Grusby, M. J.
(2005). NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression. Proc. Natl. Acad. Sci. USA
102: 2016-2021
[Abstract]
[Full Text]
-
Huang, Z., Xin, J., Coleman, J., Huang, H.
(2005). IFN-{gamma} Suppresses STAT6 Phosphorylation by Inhibiting Its Recruitment to the IL-4 Receptor. J. Immunol.
174: 1332-1337
[Abstract]
[Full Text]
-
Park, W. S., Bae, Y., Chung, D. H., Choi, Y.-L., Kim, B. K., Sung, Y. C., Choi, E. Y., Park, S. H., Jung, K. C.
(2004). T cell expression of CIITA represses Th1 immunity. Int Immunol
16: 1355-1364
[Abstract]
[Full Text]
-
Weigmann, B., Nemetz, A., Becker, C., Schmidt, J., Strand, D., Lehr, H. A., Galle, P. R., Ho, I.-C., Neurath, M. F.
(2004). A Critical Regulatory Role of Leucin Zipper Transcription Factor c-Maf in Th1-Mediated Experimental Colitis. J. Immunol.
173: 3446-3455
[Abstract]
[Full Text]
-
Diehl, S., Krahl, T., Rinaldi, L., Norton, R., Irvin, C. G., Rincon, M.
(2004). Inhibition of NFAT Specifically in T Cells Prevents Allergic Pulmonary Inflammation. J. Immunol.
172: 3597-3603
[Abstract]
[Full Text]
-
Tamauchi, H., Terashima, M., Ito, M., Maruyama, H., Ikewaki, N., Inoue, M., Gao, X., Hozumi, K., Habu, S.
(2004). Evidence of GATA-3-dependent Th2 commitment during the in vivo immune response. Int Immunol
16: 179-187
[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]
-
Valanciute, A., le Gouvello, S., Solhonne, B., Pawlak, A., Grimbert, P., Lyonnet, L., Hue, S., Lang, P., Remy, P., Salomon, R., Bensman, A., Guellaen, G., Sahali, D.
(2004). NF-{kappa}B p65 Antagonizes IL-4 Induction by c-maf in Minimal Change Nephrotic Syndrome. J. Immunol.
172: 688-698
[Abstract]
[Full Text]
-
Kaminski, B. A., Kadereit, S., Miller, R. E., Leahy, P., Stein, K. R., Topa, D. A., Radivoyevitch, T., Veigl, M. L., Laughlin, M. J.
(2003). Reduced expression of NFAT-associated genes in UCB versus adult CD4+ T lymphocytes during primary stimulation. Blood
102: 4608-4617
[Abstract]
[Full Text]
-
Sundrud, M. S., Grill, S. M., Ni, D., Nagata, K., Alkan, S. S., Subramaniam, A., Unutmaz, D.
(2003). Genetic Reprogramming of Primary Human T Cells Reveals Functional Plasticity in Th Cell Differentiation. J. Immunol.
171: 3542-3549
[Abstract]
[Full Text]
-
Grimbert, P., Valanciute, A., Audard, V., Pawlak, A., Le gouvelo, S., Lang, P., Niaudet, P., Bensman, A., Guellaen, G., Sahali, D.
(2003). Truncation of C-mip (Tc-mip), a New Proximal Signaling Protein, Induces c-maf Th2 Transcription Factor and Cytoskeleton Reorganization. JEM
198: 797-807
[Abstract]
[Full Text]
-
Komine, O., Hayashi, K., Natsume, W., Watanabe, T., Seki, Y., Seki, N., Yagi, R., Sukzuki, W., Tamauchi, H., Hozumi, K., Habu, S., Kubo, M., Satake, M.
(2003). The Runx1 Transcription Factor Inhibits the Differentiation of Naive CD4+ T Cells into the Th2 Lineage by Repressing GATA3 Expression. JEM
198: 51-61
[Abstract]
[Full Text]
-
Little, F. F., Center, D. M.
(2003). Induced Sputum Analysis For T Helper Type 2 Cell Regulation: Closing the Loop. Chest
123: 1786-1788
[Full Text]
-
Taha, R., Hamid, Q., Cameron, L., Olivenstein, R.
(2003). T Helper Type 2 Cytokine Receptors and Associated Transcription Factors GATA-3, c-MAF, and Signal Transducer and Activator of Transcription Factor-6 in Induced Sputum of Atopic Asthmatic Patients. Chest
123: 2074-2082
[Abstract]
[Full Text]
-
Grimbert, P., Audard, V., Remy, P., Lang, P., Sahali, D.
(2003). Recent approaches to the pathogenesis of minimal-change nephrotic syndrome. Nephrol Dial Transplant
18: 245-248
[Full Text]
-
Lankford, C. S. R., Frucht, D. M.
(2003). A unique role for IL-23 in promoting cellular immunity. J. Leukoc. Biol.
73: 49-56
[Abstract]
[Full Text]
-
Hwang, E. S., White, I. A., Ho, I-C.
(2002). An IL-4-independent and CD25-mediated function of c-maf in promoting the production of Th2 cytokines. Proc. Natl. Acad. Sci. USA
99: 13026-13030
[Abstract]
[Full Text]
-
Loza, M. J., Perussia, B.
(2002). Peripheral Immature CD2-/low T Cell Development from Type 2 to Type 1 Cytokine Production. J. Immunol.
169: 3061-3068
[Abstract]
[Full Text]
-
Stephensen, C. B., Rasooly, R., Jiang, X., Ceddia, M. A., Weaver, C. T., Chandraratna, R. A. S., Bucy, R. P.
(2002). Vitamin A Enhances in Vitro Th2 Development Via Retinoid X Receptor Pathway. J. Immunol.
168: 4495-4503
[Abstract]
[Full Text]
-
Brogdon, J. L., Leitenberg, D., Bottomly, K.
(2002). The Potency of TCR Signaling Differentially Regulates NFATc/p Activity and Early IL-4 Transcription in Naive CD4+ T Cells. J. Immunol.
168: 3825-3832
[Abstract]
[Full Text]
-
Frucht, D. M.
(2002). IL-23: A Cytokine That Acts on Memory T Cells. Sci Signal
2002: pe1-pe1
[Abstract]
[Full Text]
-
Kishikawa, H., Sun, J., Choi, A., Miaw, S.-C., Ho, I-C.
(2001). The Cell Type-Specific Expression of the Murine IL-13 Gene Is Regulated by GATA-3. J. Immunol.
167: 4414-4420
[Abstract]
[Full Text]
-
Chtanova, T., Kemp, R. A., Sutherland, A. P. R., Ronchese, F., Mackay, C. R.
(2001). Gene Microarrays Reveal Extensive Differential Gene Expression in Both CD4+ and CD8+ Type 1 and Type 2 T Cells. J. Immunol.
167: 3057-3063
[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]
-
Zhang, Y., Apilado, R., Coleman, J., Ben-Sasson, S., Tsang, S., Hu-Li, J., Paul, W. E., Huang, H.
(2001). Interferon {gamma} Stabilizes the T Helper Cell Type 1 Phenotype. JEM
194: 165-172
[Abstract]
[Full Text]
-
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]
-
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]
-
Lanzavecchia, A., Sallusto, F.
(2000). Dynamics of T Lymphocyte Responses: Intermediates, Effectors, and Memory Cells. Science
290: 92-97
[Abstract]
[Full Text]
-
SINIGAGLIA, F., D'AMBROSIO, D.
(2000). Regulation of Helper T Cell Differentiation and Recruitment in Airway Inflammation. Am. J. Respir. Crit. Care Med.
162: S157-160
[Abstract]
[Full Text]
-
Elhofy, A., Marriott, I., Bost, K. L.
(2000). Salmonella Infection Does Not Increase Expression and Activity of the High Affinity IL-12 Receptor. J. Immunol.
165: 3324-3332
[Abstract]
[Full Text]
-
WIERENGA, E. A., MESSER, G.
(2000). Regulation of Interleukin 4 Gene Transcription . Alterations in Atopic Disease?. Am. J. Respir. Crit. Care Med.
162: S81-85
[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]
-
Yin, Z., Zhang, D.-H., Welte, T., Bahtiyar, G., Jung, S., Liu, L., Fu, X.-Y., Ray, A., Craft, J.
(2000). Dominance of IL-12 Over IL-4 in {gamma}{delta} T Cell Differentiation Leads to Default Production of IFN-{gamma}: Failure to Down-Regulate IL-12 Receptor {beta}2-Chain Expression. J. Immunol.
164: 3056-3064
[Abstract]
[Full Text]
-
Nishikomori, R., Ehrhardt, R. O., Strober, W.
(2000). T Helper Type 2 Cell Differentiation Occurs in the Presence of Interleukin 12 Receptor {beta}2 Chain Expression and Signaling. JEM
191: 847-858
[Abstract]
[Full Text]
-
Noble, A., Truman, J. P., Vyas, B., Vukmanovic-Stejic, M., Hirst, W. J., Michael Kemeny, D.
(2000). The Balance of Protein Kinase C and Calcium Signaling Directs T Cell Subset Development. J. Immunol.
164: 1807-1813
[Abstract]
[Full Text]
-
Ring, B., Cordes, S., Overbeek, P., Barsh, G.
(2000). Regulation of mouse lens fiber cell development and differentiation by the Maf gene. Development
127: 307-317
[Abstract]
-
Kono, D. H., Balomenos, D., Park, M. S., Theofilopoulos, A. N.
(2000). Development of Lupus in BXSB Mice Is Independent of IL-4. J. Immunol.
164: 38-42
[Abstract]
[Full Text]
-
Richter, A., Lohning, M., Radbruch, A.
(1999). Instruction for Cytokine Expression in T Helper Lymphocytes in Relation to Proliferation and Cell Cycle Progression. JEM
190: 1439-1450
[Abstract]
[Full Text]
-
Aronica, M. A., Mora, A. L., Mitchell, D. B., Finn, P. W., Johnson, J. E., Sheller, J. R., Boothby, M. R.
(1999). Preferential Role for NF-{kappa}B/Rel Signaling in the Type 1 But Not Type 2 T Cell-Dependent Immune Response In Vivo. J. Immunol.
163: 5116-5124
[Abstract]
[Full Text]
-
Doyle, A. G., Buttigieg, K., Groves, P., Johnson, B. J., Kelso, A.
(1999). The Activated Type 1-Polarized Cd8+ T Cell Population Isolated from an Effector Site Contains Cells with Flexible Cytokine Profiles. JEM
190: 1081-1092
[Abstract]
[Full Text]
-
Sherman, M. A., Nachman, T. Y., Brown, M. A.
(1999). Cutting Edge: IL-4 Production by Mast Cells Does Not Require c-maf. J. Immunol.
163: 1733-1736
[Abstract]
[Full Text]
-
FLAVELL, R.A., LI, B., DONG, C., LU, H.-T., YANG, D. D., ENSLEN, H., TOURNIER, C., WHITMARSH, A., WYSK, M., CONZE, D., RINCON, M., DAVIS, R.J.
(1999). Molecular Basis of T-cell Differentiation. Cold Spring Harb Symp Quant Biol
64: 563-572
[Abstract]
-
HO, I.-C., KIM, J.I., SZABO, S.J., GLIMCHER, L.H.
(1999). Tissue-specific Regulation of Cytokine Gene Expression. Cold Spring Harb Symp Quant Biol
64: 573-584
[Abstract]