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Science 323 (5920): 1488-1492

Copyright © 2009 by the American Association for the Advancement of Science

Preferential Generation of Follicular B Helper T Cells from Foxp3+ T Cells in Gut Peyer's Patches

Masayuki Tsuji,1* Noriko Komatsu,2* Shimpei Kawamoto,1,4* Keiichiro Suzuki,1 Osami Kanagawa,3 Tasuku Honjo,4 Shohei Hori,2{dagger} Sidonia Fagarasan1{dagger}

Abstract: Most of the immunoglobulin A (IgA) in the gut is generated by B cells in the germinal centers of Peyer's patches through a process that requires the presence of CD4+ follicular B helper T(TFH) cells. The nature of these TFH cells in Peyer's patches has been elusive. Here, we demonstrate that suppressive Foxp3+CD4+ T cells can differentiate into TFH cells in mouse Peyer's patches. The conversion of Foxp3+ T cells into TFH cells requires the loss of Foxp3 expression and subsequent interaction with B cells. Thus, environmental cues present in gut Peyer's patches promote the selective differentiation of distinct helper T cell subsets, such as TFH cells.

1 Laboratory for Mucosal Immunity, RIKEN, Yokohama 1-7-22, Tsurumi, Yokohama, 230-0045, Japan.
2 Research Unit for Immune Homeostasis, RIKEN, Yokohama 1-7-22, Tsurumi, Yokohama, 230-0045, Japan.
3 Laboratory for Autoimmune Regulation, Research Center for Allergy and Immunology, RIKEN, Yokohama 1-7-22, Tsurumi, Yokohama, 230-0045, Japan.
4 Department of Immunology and Genomic Medicine, Kyoto University, Graduate School of Medicine, Sakyo-ku, Kyoto 606-8501, Japan.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: shohei{at} (S.H.); sidonia-f{at} (S.F.)

IL-21-Producing Th Cells in Immunity and Autoimmunity.
S. M. Liu and C. King (2013)
J. Immunol. 191, 3501-3506
   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 »
Retinoic acid, acting as a highly specific IgA isotype switch factor, cooperates with TGF-{beta}1 to enhance the overall IgA response.
G.-Y. Seo, Y.-S. Jang, H.-A. Kim, M.-R. Lee, M.-H. Park, S.-R. Park, J.-M. Lee, J. Choe, and P.-H. Kim (2013)
J. Leukoc. Biol. 94, 325-335
   Abstract »    Full Text »    PDF »
Plasticity within the {alpha}{beta}+CD4+ T-cell lineage: when, how and what for?.
S. M. Coomes, V. S. Pelly, and M. S. Wilson (2013)
Open Bio 3, 120157
   Abstract »    Full Text »    PDF »
Systemic Flagellin Immunization Stimulates Mucosal CD103+ Dendritic Cells and Drives Foxp3+ Regulatory T Cell and IgA Responses in the Mesenteric Lymph Node.
A. Flores-Langarica, J. L. Marshall, J. Hitchcock, C. Cook, J. Jobanputra, S. Bobat, E. A. Ross, R. E. Coughlan, I. R. Henderson, S. Uematsu, et al. (2012)
J. Immunol. 189, 5745-5754
   Abstract »    Full Text »    PDF »
Activation of B cells by non-canonical helper signals.
A. Cerutti, M. Cols, and I. Puga (2012)
EMBO Rep. 13, 798-810
   Abstract »    Full Text »    PDF »
Treg Cells, Life History, and Diversity.
C. Benoist and D. Mathis (2012)
Cold Spring Harb Perspect Biol 4, a007021
   Abstract »    Full Text »    PDF »
Neogenesis of Lymphoid Structures and Antibody Responses Occur in Human Melanoma Metastases.
A. Cipponi, M. Mercier, T. Seremet, J.-F. Baurain, I. Theate, J. van den Oord, M. Stas, T. Boon, P. G. Coulie, and N. van Baren (2012)
Cancer Res. 72, 3997-4007
   Abstract »    Full Text »    PDF »
IL-21 Promotes Lupus-like Disease in Chronic Graft-versus-Host Disease through Both CD4 T Cell- and B Cell-Intrinsic Mechanisms.
V. Nguyen, I. Luzina, H. Rus, C. Tegla, C. Chen, and V. Rus (2012)
J. Immunol. 189, 1081-1093
   Abstract »    Full Text »    PDF »
Requirement for Diverse TCR Specificities Determines Regulatory T Cell Activity in a Mouse Model of Autoimmune Arthritis.
S. Oh, M. Aitken, D. M. Simons, A. Basehoar, V. Garcia, E. Kropf, and A. J. Caton (2012)
J. Immunol. 188, 4171-4180
   Abstract »    Full Text »    PDF »
The Inhibitory Receptor PD-1 Regulates IgA Selection and Bacterial Composition in the Gut.
S. Kawamoto, T. H. Tran, M. Maruya, K. Suzuki, Y. Doi, Y. Tsutsui, L. M. Kato, and S. Fagarasan (2012)
Science 336, 485-489
   Abstract »    Full Text »    PDF »
Induced Foxp3+ regulatory T cells: a potential new weapon to treat autoimmune and inflammatory diseases?.
Q. Lan, H. Fan, V. Quesniaux, B. Ryffel, Z. Liu, and S. Guo Zheng (2012)
J Mol Cell Biol 4, 22-28
   Abstract »    Full Text »    PDF »
TGF-{beta}: the sword, the wand, and the shield of FOXP3+ regulatory T cells.
D. Q. Tran (2012)
J Mol Cell Biol 4, 29-37
   Abstract »    Full Text »    PDF »
Dominant Th2 Differentiation of Human Regulatory T Cells upon Loss of FOXP3 Expression.
L. Hansmann, C. Schmidl, J. Kett, L. Steger, R. Andreesen, P. Hoffmann, M. Rehli, and M. Edinger (2012)
J. Immunol. 188, 1275-1282
   Abstract »    Full Text »    PDF »
Rapid In Vivo Conversion of Effector T Cells into Th2 Cells during Helminth Infection.
M. Panzer, S. Sitte, S. Wirth, I. Drexler, T. Sparwasser, and D. Voehringer (2012)
J. Immunol. 188, 615-623
   Abstract »    Full Text »    PDF »
B Cell Depletion Enhances T Regulatory Cell Activity Essential in the Suppression of Arthritis.
K. M. Hamel, Y. Cao, S. Ashaye, Y. Wang, R. Dunn, M. R. Kehry, T. T. Glant, and A. Finnegan (2011)
J. Immunol. 187, 4900-4906
   Abstract »    Full Text »    PDF »
Regulation of the Germinal Center Reaction by Foxp3+ Follicular Regulatory T Cells.
I. Wollenberg, A. Agua-Doce, A. Hernandez, C. Almeida, V. G. Oliveira, J. Faro, and L. Graca (2011)
J. Immunol. 187, 4553-4560
   Abstract »    Full Text »    PDF »
SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-{gamma} and IL-17A production.
R. Takahashi, S. Nishimoto, G. Muto, T. Sekiya, T. Tamiya, A. Kimura, R. Morita, M. Asakawa, T. Chinen, and A. Yoshimura (2011)
J. Exp. Med. 208, 2055-2067
   Abstract »    Full Text »    PDF »
Blockade of B7-H1 (Programmed Death Ligand 1) Enhances Humoral Immunity by Positively Regulating the Generation of T Follicular Helper Cells.
E. Hams, M. J. McCarron, S. Amu, H. Yagita, M. Azuma, L. Chen, and P. G. Fallon (2011)
J. Immunol. 186, 5648-5655
   Abstract »    Full Text »    PDF »
Physiologic Control of the Functional Status of Foxp3+ Regulatory T Cells.
A. L. Mellor and D. H. Munn (2011)
J. Immunol. 186, 4535-4540
   Abstract »    Full Text »    PDF »
Functional Plasticity of Antigen-Specific Regulatory T Cells in Context of Tumor.
C. Addey, M. White, L. Dou, D. Coe, J. Dyson, and J.-G. Chai (2011)
J. Immunol. 186, 4557-4564
   Abstract »    Full Text »    PDF »
Is Treg Plasticity the Achilles' Heel to Their Functional Inactivation?.
S. Piconese and M. P. Colombo (2011)
Am. Assoc. Cancer Res. Educ. Book 2011, 103-108
   Full Text »    PDF »
ATP Inhibits the Generation and Function of Regulatory T Cells Through the Activation of Purinergic P2X Receptors.
U. Schenk, M. Frascoli, M. Proietti, R. Geffers, E. Traggiai, J. Buer, C. Ricordi, A. M. Westendorf, and F. Grassi (2011)
Science Signaling 4, ra12
   Abstract »    Full Text »    PDF »
PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice.
T. Okazaki, I.-m. Okazaki, J. Wang, D. Sugiura, F. Nakaki, T. Yoshida, Y. Kato, S. Fagarasan, M. Muramatsu, T. Eto, et al. (2011)
J. Exp. Med. 208, 395-407
   Abstract »    Full Text »    PDF »
Adapting functional genomic tools to metagenomic analyses: investigating the role of gut bacteria in relation to obesity.
Y. Liu, C. Zhang, L. Zhao, and C. Nardini (2010)
Briefings in Functional Genomics 9, 355-361
   Abstract »    Full Text »    PDF »
Synergistic Effect of IL-6 and IL-4 in Driving Fate Revision of Natural Foxp3+ Regulatory T Cells.
L. Kastner, D. Dwyer, and F. X.-F. Qin (2010)
J. Immunol. 185, 5778-5786
   Abstract »    Full Text »    PDF »
An Intrinsic Mechanism Predisposes Foxp3-Expressing Regulatory T Cells to Th2 Conversion In Vivo.
Y. Wang, A. Souabni, R. A. Flavell, and Y. Y. Wan (2010)
J. Immunol. 185, 5983-5992
   Abstract »    Full Text »    PDF »
Discrete TCR Repertoires and CDR3 Features Distinguish Effector and Foxp3+ Regulatory T Lymphocytes in Myelin Oligodendrocyte Glycoprotein-Induced Experimental Allergic Encephalomyelitis.
P. Nguyen, W. Liu, J. Ma, J. N. Manirarora, X. Liu, C. Cheng, and T. L. Geiger (2010)
J. Immunol. 185, 3895-3904
   Abstract »    Full Text »    PDF »
Phosphoinositide 3-Kinase Activity in T Cells Regulates the Magnitude of the Germinal Center Reaction.
J. Rolf, S. E. Bell, D. Kovesdi, M. L. Janas, D. R. Soond, L. M. C. Webb, S. Santinelli, T. Saunders, B. Hebeis, N. Killeen, et al. (2010)
J. Immunol. 185, 4042-4052
   Abstract »    Full Text »    PDF »
Stability of the Regulatory T Cell Lineage in Vivo.
Y. P. Rubtsov, R. E. Niec, S. Josefowicz, L. Li, J. Darce, D. Mathis, C. Benoist, and A. Y. Rudensky (2010)
Science 329, 1667-1671
   Abstract »    Full Text »    PDF »
Smad2 and Smad3 Are Redundantly Essential for the TGF-{beta}-Mediated Regulation of Regulatory T Plasticity and Th1 Development.
T. Takimoto, Y. Wakabayashi, T. Sekiya, N. Inoue, R. Morita, K. Ichiyama, R. Takahashi, M. Asakawa, G. Muto, T. Mori, et al. (2010)
J. Immunol. 185, 842-855
   Abstract »    Full Text »    PDF »
IgA Changes the Rules of Memory.
A. Cerutti (2010)
Science 328, 1646-1647
   Abstract »    Full Text »    PDF »
The Pathogen Recognition Receptor NOD2 Regulates Human FOXP3+ T Cell Survival.
M. K. Rahman, E. H. Midtling, P. A. Svingen, Y. Xiong, M. P. Bell, J. Tung, T. Smyrk, L. J. Egan, and W. A. Faubion Jr. (2010)
J. Immunol. 184, 7247-7256
   Abstract »    Full Text »    PDF »
CD4+CD25+Foxp3+ Regulatory T Cells Optimize Diversity of the Conventional T Cell Repertoire during Reconstitution from Lymphopenia.
C. J. Winstead, C. S. Reilly, J. J. Moon, M. K. Jenkins, S. E. Hamilton, S. C. Jameson, S. S. Way, and A. Khoruts (2010)
J. Immunol. 184, 4749-4760
   Abstract »    Full Text »    PDF »
The inducible T-cell co-stimulator molecule is expressed on subsets of T cells and is a new marker of lymphomas of T follicular helper cell-derivation.
T. Marafioti, J. C. Paterson, E. Ballabio, A. Chott, Y. Natkunam, M. Rodriguez-Justo, A. Plonquet, S. M. Rodriguez-Pinilla, W. Klapper, M.-L. Hansmann, et al. (2010)
Haematologica 95, 432-439
   Abstract »    Full Text »    PDF »
Mechanisms Underlying Lineage Commitment and Plasticity of Helper CD4+ T Cells.
J. J. O'Shea and W. E. Paul (2010)
Science 327, 1098-1102
   Abstract »    Full Text »    PDF »
IL-21 and T follicular helper cells.
R. Spolski and W. J. Leonard (2010)
Int. Immunol. 22, 7-12
   Abstract »    Full Text »    PDF »
Anti-CTLA-4 treatment induces IL-10-producing ICOS+ regulatory T cells displaying IDO-dependent anti-inflammatory properties in a mouse model of colitis.
C Coquerelle, G Oldenhove, V Acolty, J Denoeud, G Vansanten, J-M Verdebout, A Mellor, J A Bluestone, and M Moser (2009)
Gut 58, 1363-1373
   Abstract »    Full Text »    PDF »
Polyps Wrap Mast Cells and Treg within Tumorigenic Tentacles.
M. P. Colombo and S. Piconese (2009)
Cancer Res. 69, 5619-5622
   Abstract »    Full Text »    PDF »

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