Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 30 June 2000:
Vol. 288. no. 5475, pp. 2369 - 2373
DOI: 10.1126/science.288.5475.2369
Prev | Table of Contents | Next

Reports

Requirement for RORgamma in Thymocyte Survival and Lymphoid Organ Development

Zuoming Sun, 1 Derya Unutmaz, 1 Yong-Rui Zou, 1 Mary Jean Sunshine, 12 Alessandra Pierani, 3 Susan Brenner-Morton, 34 Reina E. Mebius, 5 Dan R. Littman 12*

Most developing thymocytes undergo apoptosis because they cannot interact productively with molecules encoded by the major histocompatibility complex. Here, we show that mice lacking the orphan nuclear hormone receptor RORgamma lose thymic expression of the anti-apoptotic factor Bcl-xL. RORgamma thus regulates the survival of CD4+8+ thymocytes and may control the temporal window during which thymocytes can undergo positive selection. RORgamma was also required for development of lymph nodes and Peyer's patches, but not splenic follicles. In its absence, there was loss of a population of CD3-CD4+CD45+ cells that normally express RORgamma and that are likely early progenitors of lymphoid organs. Hence, RORgamma has critical functions in T cell repertoire selection and lymphoid organogenesis.

1 Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine and
2 Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.
3 Department of Biochemistry and Molecular Biophysics and
4 Howard Hughes Medical Institute, Columbia University, New York, NY 10032, USA.
5 Faculty of Medicine, Department of Cell Biology and Immunology, Vrije Universiteit, 1081 BT Amsterdam, Netherlands.
*   To whom correspondence should be addressed. E-mail: littman{at}saturn.med.nyu.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Id2-, ROR{gamma}t-, and LT{beta}R-independent initiation of lymphoid organogenesis in ocular immunity.
T. Nagatake, S. Fukuyama, D.-Y. Kim, K. Goda, O. Igarashi, S. Sato, T. Nochi, H. Sagara, Y. Yokota, A. M. Jetten, et al. (2009)
J. Exp. Med. 206, 2351-2364
   Abstract »    Full Text »    PDF »
Cutting Edge: IL-7 Regulates the Peripheral Pool of Adult ROR{gamma}+ Lymphoid Tissue Inducer Cells.
S. Schmutz, N. Bosco, S. Chappaz, O. Boyman, H. Acha-Orbea, R. Ceredig, A. G. Rolink, and D. Finke (2009)
J. Immunol. 183, 2217-2221
   Abstract »    Full Text »    PDF »
Stage 3 immature human natural killer cells found in secondary lymphoid tissue constitutively and selectively express the TH17 cytokine interleukin-22.
T. Hughes, B. Becknell, S. McClory, E. Briercheck, A. G. Freud, X. Zhang, H. Mao, G. Nuovo, J. Yu, and M. A. Caligiuri (2009)
Blood 113, 4008-4010
   Abstract »    Full Text »    PDF »
Identification of IL-17-producing FOXP3+ regulatory T cells in humans.
K. S. Voo, Y.-H. Wang, F. R. Santori, C. Boggiano, Y.-H. Wang, K. Arima, L. Bover, S. Hanabuchi, J. Khalili, E. Marinova, et al. (2009)
PNAS 106, 4793-4798
   Abstract »    Full Text »    PDF »
Lymph sacs are not required for the initiation of lymph node formation.
M. F. Vondenhoff, S. A. van de Pavert, M. E. Dillard, M. Greuter, G. Goverse, G. Oliver, and R. E. Mebius (2009)
Development 136, 29-34
   Abstract »    Full Text »    PDF »
Clock-dependent and independent transcriptional control of the two isoforms from the mouse Rorgammagene..
V. Mongrain, X. Ruan, H. Dardente, E. E. Fortier, and N. Cermakian (2008)
Genes Cells 13, 1197-1210
   Abstract »    Full Text »    PDF »
Identification of CD25+ {gamma}{delta} T Cells As Fetal Thymus-Derived Naturally Occurring IL-17 Producers.
K. Shibata, H. Yamada, R. Nakamura, X. Sun, M. Itsumi, and Y. Yoshikai (2008)
J. Immunol. 181, 5940-5947
   Abstract »    Full Text »    PDF »
Organizer-Like Reticular Stromal Cell Layer Common to Adult Secondary Lymphoid Organs.
T. Katakai, H. Suto, M. Sugai, H. Gonda, A. Togawa, S. Suematsu, Y. Ebisuno, K. Katagiri, T. Kinashi, and A. Shimizu (2008)
J. Immunol. 181, 6189-6200
   Abstract »    Full Text »    PDF »
The Emerging Role of Nuclear Receptor ROR{alpha} and Its Crosstalk with LXR in Xeno- and Endobiotic Gene Regulation.
T. Wada, H. S. Kang, A. M. Jetten, and W. Xie (2008)
Experimental Biology and Medicine 233, 1191-1201
   Abstract »    Full Text »    PDF »
Tumor-specific Th17-polarized cells eradicate large established melanoma.
P. Muranski, A. Boni, P. A. Antony, L. Cassard, K. R. Irvine, A. Kaiser, C. M. Paulos, D. C. Palmer, C. E. Touloukian, K. Ptak, et al. (2008)
Blood 112, 362-373
   Abstract »    Full Text »    PDF »
Isoform-Specific Inhibition of ROR{alpha}-Mediated Transcriptional Activation by Human FOXP3.
J. Du, C. Huang, B. Zhou, and S. F. Ziegler (2008)
J. Immunol. 180, 4785-4792
   Abstract »    Full Text »    PDF »
Normal development is an integral part of tumorigenesis in T cell-specific PTEN-deficient mice.
L. Xue, H. Nolla, A. Suzuki, T. W. Mak, and A. Winoto (2008)
PNAS 105, 2022-2027
   Abstract »    Full Text »    PDF »
BCL11B is required for positive selection and survival of double-positive thymocytes.
D. I. Albu, D. Feng, D. Bhattacharya, N. A. Jenkins, N. G. Copeland, P. Liu, and D. Avram (2007)
J. Exp. Med. 204, 3003-3015
   Abstract »    Full Text »    PDF »
Effect of presenilins in the apoptosis of thymocytes and homeostasis of CD8+ T cells.
A. Maraver, C. E. Tadokoro, M. L. Badura, J. Shen, M. Serrano, and J. J. Lafaille (2007)
Blood 110, 3218-3225
   Abstract »    Full Text »    PDF »
Gene expression profiling reveals a regulatory role for ROR{alpha} and ROR{gamma} in phase I and phase II metabolism.
H. S. Kang, M. Angers, J. Y. Beak, X. Wu, J. M. Gimble, T. Wada, W. Xie, J. B. Collins, S. F. Grissom, and A. M. Jetten (2007)
Physiol Genomics 31, 281-294
   Abstract »    Full Text »    PDF »
Distinct roles for Syk and ZAP-70 during early thymocyte development.
E. H. Palacios and A. Weiss (2007)
J. Exp. Med. 204, 1703-1715
   Abstract »    Full Text »    PDF »
Retinoid-Related Orphan Receptor {gamma} Controls Immunoglobulin Production and Th1/Th2 Cytokine Balance in the Adaptive Immune Response to Allergen.
S. L. Tilley, M. Jaradat, C. Stapleton, D. Dixon, X. Hua, C. J. Erikson, J. G. McCaskill, K. D. Chason, G. Liao, L. Jania, et al. (2007)
J. Immunol. 178, 3208-3218
   Abstract »    Full Text »    PDF »
Function of CD4+CD3- cells in relation to B- and T-zone stroma in spleen.
M.-Y. Kim, F. M. McConnell, F. M. C. Gaspal, A. White, S. H. Glanville, V. Bekiaris, L. S. K. Walker, J. Caamano, E. Jenkinson, G. Anderson, et al. (2007)
Blood 109, 1602-1610
   Abstract »    Full Text »    PDF »
The Effect of Genetic Variation of the Retinoic Acid Receptor-Related Orphan Receptor C Gene on Fatness in Cattle.
W. Barendse, R. J. Bunch, J. W. Kijas, and M. B. Thomas (2007)
Genetics 175, 843-853
   Abstract »    Full Text »    PDF »
Role for rearranged variable gene segments in directing secondary T cell receptor {alpha} recombination.
A. Hawwari and M. S. Krangel (2007)
PNAS 104, 903-907
   Abstract »    Full Text »    PDF »
International Union of Pharmacology. LXVI. Orphan Nuclear Receptors.
G. Benoit, A. Cooney, V. Giguere, H. Ingraham, M. Lazar, G. Muscat, T. Perlmann, J.-P. Renaud, J. Schwabe, F. Sladek, et al. (2006)
Pharmacol. Rev. 58, 798-836
   Abstract »    Full Text »    PDF »
Molecular components of the mammalian circadian clock.
C. H. Ko and J. S. Takahashi (2006)
Hum. Mol. Genet. 15, R271-R277
   Abstract »    Full Text »    PDF »
Neonatal and Adult CD4+CD3- Cells Share Similar Gene Expression Profile, and Neonatal Cells Up-Regulate OX40 Ligand in Response to TL1A (TNFSF15)..
M.-Y. Kim, K.-M. Toellner, A. White, F. M. McConnell, F. M. C. Gaspal, S. M. Parnell, E. Jenkinson, G. Anderson, and P. J. L. Lane (2006)
J. Immunol. 177, 3074-3081
   Abstract »    Full Text »    PDF »
Abnormal lymphoid organ development in immunodeficient mutant mice..
R. Seymour, J. P. Sundberg, and H. HogenEsch (2006)
Vet. Pathol. 43, 401-423
   Abstract »    Full Text »    PDF »
Stabilized {beta}-Catenin Extends Thymocyte Survival by Up-Regulating Bcl-xL.
H. Xie, Z. Huang, M. S. Sadim, and Z. Sun (2005)
J. Immunol. 175, 7981-7988
   Abstract »    Full Text »    PDF »
Genetically Modified Animals in Endocrinology.
(2005)
Endocr. Rev. 26, 985-993
   Abstract »    Full Text »    PDF »
Role of CXC Chemokine Ligand 13, CC Chemokine Ligand (CCL) 19, and CCL21 in the Organization and Function of Nasal-Associated Lymphoid Tissue.
J. Rangel-Moreno, J. Moyron-Quiroz, K. Kusser, L. Hartson, H. Nakano, and T. D. Randall (2005)
J. Immunol. 175, 4904-4913
   Abstract »    Full Text »    PDF »
Reduction of Runx1 Transcription Factor Activity Up-Regulates Fas and Bim Expression and Enhances the Apoptotic Sensitivity of Double Positive Thymocytes.
N. Abe, K. Kohu, H. Ohmori, K. Hayashi, T. Watanabe, K. Hozumi, T. Sato, S. Habu, and M. Satake (2005)
J. Immunol. 175, 4475-4482
   Abstract »    Full Text »    PDF »
ROR{gamma}t Recruits Steroid Receptor Coactivators to Ensure Thymocyte Survival.
H. Xie, M. S. Sadim, and Z. Sun (2005)
J. Immunol. 175, 3800-3809
   Abstract »    Full Text »    PDF »
OX40 Ligand and CD30 Ligand Are Expressed on Adult but Not Neonatal CD4+CD3- Inducer Cells: Evidence That IL-7 Signals Regulate CD30 Ligand but Not OX40 Ligand Expression.
M.-Y. Kim, G. Anderson, A. White, E. Jenkinson, W. Arlt, I.-L. Martensson, L. Erlandsson, and P. J. L. Lane (2005)
J. Immunol. 174, 6686-6691
   Abstract »    Full Text »    PDF »
The Antiapoptotic Protein Bcl-xL Is Dispensable for the Development of Effector and Memory T Lymphocytes.
N. Zhang and Y.-W. He (2005)
J. Immunol. 174, 6967-6973
   Abstract »    Full Text »    PDF »
Commitment toward the natural T (iNKT) cell lineage occurs at the CD4+8+ stage of thymic ontogeny.
J. S. Bezbradica, T. Hill, A. K. Stanic, L. Van Kaer, and S. Joyce (2005)
PNAS 102, 5114-5119
   Abstract »    Full Text »    PDF »
Lymphotoxin-Mediated Regulation of {gamma}{delta} Cell Differentiation by {alpha}{beta} T Cell Progenitors.
B. Silva-Santos, D. J. Pennington, and A. C. Hayday (2005)
Science 307, 925-928
   Abstract »    Full Text »    PDF »
Cellular Interactions in Lymph Node Development.
T. Cupedo and R. E. Mebius (2005)
J. Immunol. 174, 21-25
   Abstract »    Full Text »    PDF »
Intestinal Cryptopatch Formation in Mice Requires Lymphotoxin {alpha} and the Lymphotoxin {beta} Receptor.
R. T. Taylor, A. Lugering, K. A. Newell, and I. R. Williams (2004)
J. Immunol. 173, 7183-7189
   Abstract »    Full Text »    PDF »
IL-7 Receptor Signals Inhibit Expression of Transcription Factors TCF-1, LEF-1, and ROR{gamma}t: Impact on Thymocyte Development.
Q. Yu, B. Erman, J.-H. Park, L. Feigenbaum, and A. Singer (2004)
J. Exp. Med. 200, 797-803
   Abstract »    Full Text »    PDF »
Lymphocyte Development and Function in the Absence of Retinoic Acid-Related Orphan Receptor {alpha}.
I. Dzhagalov, V. Giguere, and Y.-W. He (2004)
J. Immunol. 173, 2952-2959
   Abstract »    Full Text »    PDF »
Gene expression profiles during human CD4+ T cell differentiation.
M. S. Lee, K. Hanspers, C. S. Barker, A. P. Korn, and J. M. McCune (2004)
Int. Immunol. 16, 1109-1124
   Abstract »    Full Text »    PDF »
Thymic Origin of Intestinal {alpha}{beta} T Cells Revealed by Fate Mapping of ROR{gamma}t+ Cells.
G. Eberl and D. R. Littman (2004)
Science 305, 248-251
   Abstract »    Full Text »    PDF »
Sustained Early Growth Response Gene 3 Expression Inhibits the Survival of CD4/CD8 Double-Positive Thymocytes.
H. Xi and G. J. Kersh (2004)
J. Immunol. 173, 340-348
   Abstract »    Full Text »    PDF »
Ror{gamma} (Rorc) Is a Common Integration Site in Type B Leukemogenic Virus-Induced T-Cell Lymphomas.
D. R. Broussard, M. M. Lozano, and J. P. Dudley (2004)
J. Virol. 78, 4943-4946
   Abstract »    Full Text »    PDF »
Modulating the intestinal immune system: the role of lymphotoxin and GALT organs.
T W Spahn and T Kucharzik (2004)
Gut 53, 456-465
   Full Text »    PDF »
Lymphocyte Accumulation in the Spleen of Retinoic Acid Receptor-Related Orphan Receptor {gamma}-Deficient Mice.
N. Zhang, J. Guo, and Y.-W. He (2003)
J. Immunol. 171, 1667-1675
   Abstract »    Full Text »    PDF »
Identification of Reverbalpha as a Novel RORalpha Target Gene.
P. Delerive, W. W. Chin, and C. S. Suen (2002)
J. Biol. Chem. 277, 35013-35018
   Abstract »    Full Text »    PDF »
Orphan nuclear receptors in T lymphocyte development.
Y.-W. He (2002)
J. Leukoc. Biol. 72, 440-446
   Abstract »    Full Text »    PDF »
Characterization of the Retinoid Orphan-Related Receptor-{alpha} Coactivator Binding Interface: A Structural Basis for Ligand-Independent Transcription.
J. M. Harris, P. Lau, S. L. Chen, and G. E. O. Muscat (2002)
Mol. Endocrinol. 16, 998-1012
   Abstract »    Full Text »    PDF »
High Incidence of T-Cell Lymphomas in Mice Deficient in the Retinoid-related Orphan Receptor ROR{gamma}.
E. Ueda, S. Kurebayashi, M. Sakaue, M. Backlund, B. Koller, and A. M. Jetten (2002)
Cancer Res. 62, 901-909
   Abstract »    Full Text »    PDF »
Cutting Edge: Organogenesis of Nasal-Associated Lymphoid Tissue (NALT) Occurs Independently of Lymphotoxin-{alpha} (LT{alpha}) and Retinoic Acid Receptor-Related Orphan Receptor-{gamma}, but the Organization of NALT Is LT{alpha} Dependent.
A. Harmsen, K. Kusser, L. Hartson, M. Tighe, M. J. Sunshine, J. D. Sedgwick, Y. Choi, D. R. Littman, and T. D. Randall (2002)
J. Immunol. 168, 986-990
   Abstract »    Full Text »    PDF »
Requirement for the NF-{kappa}B Family Member RelA in the Development of Secondary Lymphoid Organs.
E. Alcamo, N. Hacohen, L. C. Schulte, P. D. Rennert, R. O. Hynes, and D. Baltimore (2002)
J. Exp. Med. 195, 233-244
   Abstract »    Full Text »    PDF »
The Fetal Liver Counterpart of Adult Common Lymphoid Progenitors Gives Rise to All Lymphoid Lineages, CD45+CD4+CD3- Cells, As Well As Macrophages.
R. E. Mebius, T. Miyamoto, J. Christensen, J. Domen, T. Cupedo, I. L. Weissman, and K. Akashi (2001)
J. Immunol. 166, 6593-6601
   Abstract »    Full Text »    PDF »
Lymphoid neogenesis: de novo formation of lymphoid tissue in chronic inflammation through expression of homing chemokines.
P. Hjelmström (2001)
J. Leukoc. Biol. 69, 331-339
   Abstract »    Full Text »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)