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.

Subscribe

Logo for

Science 329 (5993): 849-853

Copyright © 2010 by the American Association for the Advancement of Science

Activation of β-Catenin in Dendritic Cells Regulates Immunity Versus Tolerance in the Intestine

Santhakumar Manicassamy,1 Boris Reizis,2 Rajesh Ravindran,1 Helder Nakaya,1 Rosa Maria Salazar-Gonzalez,1,3 Yi-chong Wang,1 Bali Pulendran1,4,*

Abstract: Dendritic cells (DCs) play a vital role in initiating robust immunity against pathogens as well as maintaining immunological tolerance to self antigens. However, the intracellular signaling networks that program DCs to become tolerogenic remain unknown. We report here that the Wnt–β-catenin signaling in intestinal dendritic cells regulates the balance between inflammatory versus regulatory responses in the gut. β-catenin in intestinal dendritic cells was required for the expression of anti-inflammatory mediators such as retinoic acid–metabolizing enzymes, interleukin-10, and transforming growth factor–β, and the stimulation of regulatory T cell induction while suppressing inflammatory effector T cells. Furthermore, ablation of β-catenin expression in DCs enhanced inflammatory responses and disease in a mouse model of inflammatory bowel disease. Thus, β-catenin signaling programs DCs to a tolerogenic state, limiting the inflammatory response.

1 Emory Vaccine Center, and Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, GA 30329, USA.
2 Department of Microbiology, Columbia University Medical Center, New York, NY 10032, USA.
3 Molecular Immunology Division, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229–3039, USA.
4 Department of Pathology, Emory University, 1364 Clifton Road NE, Atlanta, GA 30322, USA.

* To whom correspondence should be addressed. E-mail: bpulend{at}emory.edu


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Microbiota-Dependent Crosstalk Between Macrophages and ILC3 Promotes Intestinal Homeostasis.
A. Mortha, A. Chudnovskiy, D. Hashimoto, M. Bogunovic, S. P. Spencer, Y. Belkaid, and M. Merad (2014)
Science 343, 1249288
   Abstract »    Full Text »    PDF »
Novel Mechanisms Underlying the Immediate and Transient Global Tolerization of Splenic Dendritic Cells after Vaccination with a Self-Antigen.
A. M. Farkas and O. J. Finn (2014)
J. Immunol. 192, 658-665
   Abstract »    Full Text »    PDF »
{beta}-Catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8+ T cells.
X. Liang, C. Fu, W. Cui, J. L. Ober-Blobaum, S. P. Zahner, P. A. Shrikant, B. E. Clausen, R. A. Flavell, I. Mellman, and A. Jiang (2014)
J. Leukoc. Biol. 95, 179-190
   Abstract »    Full Text »    PDF »
Helicobacter pylori Cytotoxin-Associated Gene A Impairs Human Dendritic Cell Maturation and Function through IL-10-Mediated Activation of STAT3.
R. Kaebisch, R. Mejias-Luque, C. Prinz, and M. Gerhard (2014)
J. Immunol. 192, 316-323
   Abstract »    Full Text »    PDF »
Wnt6 Is Expressed in Granulomatous Lesions of Mycobacterium tuberculosis-Infected Mice and Is Involved in Macrophage Differentiation and Proliferation.
K. Schaale, J. Brandenburg, A. Kispert, M. Leitges, S. Ehlers, and N. Reiling (2013)
J. Immunol. 191, 5182-5195
   Abstract »    Full Text »    PDF »
Mucus Coat, a Dress Code for Tolerance.
Y. Belkaid and J. Grainger (2013)
Science 342, 432-433
   Abstract »    Full Text »    PDF »
Mucus Enhances Gut Homeostasis and Oral Tolerance by Delivering Immunoregulatory Signals.
M. Shan, M. Gentile, J. R. Yeiser, A. C. Walland, V. U. Bornstein, K. Chen, B. He, L. Cassis, A. Bigas, M. Cols, et al. (2013)
Science 342, 447-453
   Abstract »    Full Text »    PDF »
Antimicrobial peptides and gut microbiota in homeostasis and pathology.
M. J. Ostaff, E. F. Stange, and J. Wehkamp (2013)
EMBO Mol Med. 5, 1465-1483
   Abstract »    Full Text »    PDF »
Soluble E-cadherin in Systemic Lupus Erythematosus.
T. Jin, K. Almehed, Y. Zhu, H. Carlsten, and H. Forsblad-d'Elia (2013)
J Rheumatol 40, 1677-1682
   Abstract »    Full Text »    PDF »
Denileukin diftitox (ONTAK) induces a tolerogenic phenotype in dendritic cells and stimulates survival of resting Treg.
A. S. Baur, M. B. Lutz, S. Schierer, L. Beltrame, G. Theiner, E. Zinser, C. Ostalecki, G. Heidkamp, I. Haendle, M. Erdmann, et al. (2013)
Blood 122, 2185-2194
   Abstract »    Full Text »    PDF »
Location, location, location: tissue-specific regulation of immune responses.
W. Hu and C. Pasare (2013)
J. Leukoc. Biol. 94, 409-421
   Abstract »    Full Text »    PDF »
Early Phosphoproteomic Changes in the Mouse Spleen During Deoxynivalenol-Induced Ribotoxic Stress.
X. Pan, D. A. Whitten, M. Wu, C. Chan, C. G. Wilkerson, and J. J. Pestka (2013)
Toxicol. Sci. 135, 129-143
   Abstract »    Full Text »    PDF »
Control of T Cell Fates and Immune Tolerance by p38{alpha} Signaling in Mucosal CD103+ Dendritic Cells.
G. Huang, Y. Wang, and H. Chi (2013)
J. Immunol. 191, 650-659
   Abstract »    Full Text »    PDF »
Canonical and Noncanonical Wnt Proteins Program Dendritic Cell Responses for Tolerance.
C. Oderup, M. LaJevic, and E. C. Butcher (2013)
J. Immunol. 190, 6126-6134
   Abstract »    Full Text »    PDF »
SWAP-70 Restricts Spontaneous Maturation of Dendritic Cells.
C. Ocana-Morgner, A. Gotz, C. Wahren, and R. Jessberger (2013)
J. Immunol. 190, 5545-5558
   Abstract »    Full Text »    PDF »
Hepatic Stellate Cells Preferentially Induce Foxp3+ Regulatory T Cells by Production of Retinoic Acid.
R. M. Dunham, M. Thapa, V. M. Velazquez, E. J. Elrod, T. L. Denning, B. Pulendran, and A. Grakoui (2013)
J. Immunol. 190, 2009-2016
   Abstract »    Full Text »    PDF »
Langerhans cell homeostasis in mice is dependent on mTORC1 but not mTORC2 function.
B. Kellersch and T. Brocker (2013)
Blood 121, 298-307
   Abstract »    Full Text »    PDF »
Inhibition of WISE Preserves Renal Allograft Function.
X. Qian, X. Yuan, S. Vonderfecht, X. Ge, J. Lee, A. Jurisch, L. Zhang, A. You, V. D. Fitzpatrick, A. Williams, et al. (2013)
J. Am. Soc. Nephrol. 24, 66-76
   Abstract »    Full Text »    PDF »
Immune Suppression and Resistance Mediated by Constitutive Activation of Wnt/{beta}-Catenin Signaling in Human Melanoma Cells.
T. Yaguchi, Y. Goto, K. Kido, H. Mochimaru, T. Sakurai, N. Tsukamoto, C. Kudo-Saito, T. Fujita, H. Sumimoto, and Y. Kawakami (2012)
J. Immunol. 189, 2110-2117
   Abstract »    Full Text »    PDF »
Dendritic Cells: Arbiters of Immunity and Immunological Tolerance.
K. L. Lewis and B. Reizis (2012)
Cold Spring Harb Perspect Biol 4, a007401
   Abstract »    Full Text »    PDF »
{alpha}-1 Antitrypsin Promotes Semimature, IL-10-Producing and Readily Migrating Tolerogenic Dendritic Cells.
E. Ozeri, M. Mizrahi, G. Shahaf, and E. C. Lewis (2012)
J. Immunol. 189, 146-153
   Abstract »    Full Text »    PDF »
Zbtb46 expression distinguishes classical dendritic cells and their committed progenitors from other immune lineages.
A. T. Satpathy, W. KC, J. C. Albring, B. T. Edelson, N. M. Kretzer, D. Bhattacharya, T. L. Murphy, and K. M. Murphy (2012)
J. Exp. Med. 209, 1135-1152
   Abstract »    Full Text »    PDF »
Cutting Edge: mTORC1 in Intestinal CD11c+CD11b+ Dendritic Cells Regulates Intestinal Homeostasis by Promoting IL-10 Production.
M. Ohtani, T. Hoshii, H. Fujii, S. Koyasu, A. Hirao, and S. Matsuda (2012)
J. Immunol. 188, 4736-4740
   Abstract »    Full Text »    PDF »
Nuclear Hormone Receptors Enable Macrophages and Dendritic Cells to Sense Their Lipid Environment and Shape Their Immune Response.
L. Nagy, A. Szanto, I. Szatmari, and L. Szeles (2012)
Physiol Rev 92, 739-789
   Abstract »    Full Text »    PDF »
Intestinal CX3C chemokine receptor 1high (CX3CR1high) myeloid cells prevent T-cell-dependent colitis.
H. Kayama, Y. Ueda, Y. Sawa, S. G. Jeon, J. S. Ma, R. Okumura, A. Kubo, M. Ishii, T. Okazaki, M. Murakami, et al. (2012)
PNAS 109, 5010-5015
   Abstract »    Full Text »    PDF »
TREM2 and {beta}-Catenin Regulate Bone Homeostasis by Controlling the Rate of Osteoclastogenesis.
K. Otero, M. Shinohara, H. Zhao, M. Cella, S. Gilfillan, A. Colucci, R. Faccio, F. P. Ross, S. L. Teitelbaum, H. Takayanagi, et al. (2012)
J. Immunol. 188, 2612-2621
   Abstract »    Full Text »    PDF »
Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs.
J. Van den Bossche, B. Malissen, A. Mantovani, P. De Baetselier, and J. A. Van Ginderachter (2012)
Blood 119, 1623-1633
   Abstract »    Full Text »    PDF »
Activation of Wnt Signaling Arrests Effector Differentiation in Human Peripheral and Cord Blood-Derived T Lymphocytes.
S. Muralidharan, P. J. Hanley, E. Liu, R. Chakraborty, C. Bollard, E. Shpall, C. Rooney, B. Savoldo, J. Rodgers, and G. Dotti (2011)
J. Immunol. 187, 5221-5232
   Abstract »    Full Text »    PDF »
Pathogen-specific TLR2 Protein Activation Programs Macrophages to Induce Wnt-{beta}-Catenin Signaling.
K. Bansal, J. Trinath, D. Chakravortty, S. A. Patil, and K. N. Balaji (2011)
J. Biol. Chem. 286, 37032-37044
   Abstract »    Full Text »    PDF »
Wnt5a Skews Dendritic Cell Differentiation to an Unconventional Phenotype with Tolerogenic Features.
J. Valencia, C. Hernandez-Lopez, V. G. Martinez, L. Hidalgo, A. G. Zapata, A. Vicente, A. Varas, and R. Sacedon (2011)
J. Immunol. 187, 4129-4139
   Abstract »    Full Text »    PDF »
Cell-intrinsic role for IFN-{alpha}-STAT1 signals in regulating murine Peyer patch plasmacytoid dendritic cells and conditioning an inflammatory response.
H. S. Li, A. Gelbard, G. J. Martinez, E. Esashi, H. Zhang, H. Nguyen-Jackson, Y.-J. Liu, W. W. Overwijk, and S. S. Watowich (2011)
Blood 118, 3879-3889
   Abstract »    Full Text »    PDF »
Cutting Edge: {beta}-Catenin Is Dispensable for T Cell Effector Differentiation, Memory Formation, and Recall Responses.
M. Prlic and M. J. Bevan (2011)
J. Immunol. 187, 1542-1546
   Abstract »    Full Text »    PDF »
Comment on "Activation of {beta}-Catenin in Dendritic Cells Regulates Immunity Versus Tolerance in the Intestine".
K. M. Murphy (2011)
Science 333, 405
   Abstract »    Full Text »    PDF »
Response to Comment on "Activation of {beta}-Catenin in Dendritic Cells Regulates Immunity Versus Tolerance in the Intestine".
S. Manicassamy and B. Pulendran (2011)
Science 333, 405
   Abstract »    Full Text »    PDF »
Functional Specializations of Intestinal Dendritic Cell and Macrophage Subsets That Control Th17 and Regulatory T Cell Responses Are Dependent on the T Cell/APC Ratio, Source of Mouse Strain, and Regional Localization.
T. L. Denning, B. A. Norris, O. Medina-Contreras, S. Manicassamy, D. Geem, R. Madan, C. L. Karp, and B. Pulendran (2011)
J. Immunol. 187, 733-747
   Abstract »    Full Text »    PDF »
{beta}-Catenin Balances Immunity.
I. Mellman and B. E. Clausen (2010)
Science 329, 767-769
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882