Shared and Unique Features Distinguishing Follicular T Helper and Regulatory Cells of Peripheral Lymph Node and Peyer’s Patches

Georgiev, Hristo; Ravens, Inga; Papadogianni, Georgia; Halle, Stephan; Malissen, Bernard; Loots, Gabriela G.; Förster, Reinhold; Bernhardt, Günter

doi:10.3389/fimmu.2018.00714

Title: Shared and Unique Features Distinguishing Follicular T Helper and Regulatory Cells of Peripheral Lymph Node and Peyer’s Patches

Journal Article · 09 April 2018 · Frontiers in Immunology

DOI: https://doi.org/10.3389/fimmu.2018.00714 · OSTI ID:1432391

Georgiev, Hristo; Ravens, Inga; Papadogianni, Georgia; Halle, Stephan; Malissen, Bernard; Loots, Gabriela G.; Förster, Reinhold; Bernhardt, Günter

Follicular helper (TFH) and regulatory (TFR) cells are essential players in managing germinal center (GC) reactions that accomplish effective humoral immune responses. Transcriptome analyses were done comparing gene regulation of TFH and TFR cells isolated from Peyer’s Patches (PP) and immunized peripheral lymph nodes (pLNs) revealing many regulatory patterns common to all follicular cells. Yet, in contrast to TFH cells, the upregulation or downregulation of many genes was attenuated substantially in pLN TFR cells when compared to those of PP. Additionally, PP but not pLN TFR cells were largely unresponsive to IL2 and expressed Il4 as well as Il21. Together with fundamental differences in gene expression that were found between cells of both compartments this emphasizes specific adaptations of follicular T cell functions to their micro-milieu. Furthermore, although GL7 expression distinguishes matured follicular T cells, GL7⁺ as well as GL7^– cells are present in the GC.

View Journal Article

Cite

Export

Save

Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 1432391

Alternate ID(s):: OSTI ID: 1527289

Report Number(s):: LLNL-JRNL-741132; 714

Journal Information:: Frontiers in Immunology, Journal Name: Frontiers in Immunology Vol. 9; ISSN 1664-3224

Publisher:: Frontiers Media SACopyright Statement

Country of Publication:: Switzerland

Language:: English

References (67)

A distinct subpopulation of CD25 ⁻ T-follicular regulatory cells localizes in the germinal centers Wing, James Badger; Kitagawa, Yohko; Locci, Michela Proceedings of the National Academy of Sciences, Vol. 114, Issue 31 https://doi.org/10.1073/pnas.1705551114	journal	July 2017
CCAAT/Enhancer-binding Protein α (C/EBPα) Is Critical for Interleukin-4 Expression in Response to FcϵRI Receptor Cross-linking Qi, Xiaopeng; Nishida, Jun; Chaves, Lee Journal of Biological Chemistry, Vol. 286, Issue 18 https://doi.org/10.1074/jbc.M110.213389	journal	March 2011
How T Cells Earn the Follicular Rite of Passage Vinuesa, Carola G.; Cyster, Jason G. Immunity, Vol. 35, Issue 5 https://doi.org/10.1016/j.immuni.2011.11.001	journal	November 2011
Foxp3+ T Cells Regulate Immunoglobulin A Selection and Facilitate Diversification of Bacterial Species Responsible for Immune Homeostasis Kawamoto, Shimpei; Maruya, Mikako; Kato, Lucia M. Immunity, Vol. 41, Issue 1 https://doi.org/10.1016/j.immuni.2014.05.016	journal	July 2014
Suppression by TFR cells leads to durable and selective inhibition of B cell effector function Sage, Peter T.; Ron-Harel, Noga; Juneja, Vikram R. Nature Immunology, Vol. 17, Issue 12 https://doi.org/10.1038/ni.3578	journal	October 2016
Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development Liu, Xindong; Chen, Xin; Zhong, Bo Nature, Vol. 507, Issue 7493 https://doi.org/10.1038/nature12910	journal	January 2014
Bach2–Batf interactions control Th2-type immune response by regulating the IL-4 amplification loop Kuwahara, Makoto; Ise, Wataru; Ochi, Mizuki Nature Communications, Vol. 7, Issue 1 https://doi.org/10.1038/ncomms12596	journal	September 2016
A Fundamental Role for Interleukin-21 in the Generation of T Follicular Helper Cells Vogelzang, Alexis; McGuire, Helen M.; Yu, Di Immunity, Vol. 29, Issue 1 https://doi.org/10.1016/j.immuni.2008.06.001	journal	July 2008
T follicular helper and T follicular regulatory cells have different TCR specificity Maceiras, Ana Raquel; Almeida, Silvia Cristina Paiva; Mariotti-Ferrandiz, Encarnita Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/ncomms15067	journal	April 2017
SATB1 Expression Governs Epigenetic Repression of PD-1 in Tumor-Reactive T Cells Stephen, Tom L.; Payne, Kyle K.; Chaurio, Ricardo A. Immunity, Vol. 46, Issue 1 https://doi.org/10.1016/j.immuni.2016.12.015	journal	January 2017
T Follicular Helper Cell Differentiation, Function, and Roles in Disease Crotty, Shane Immunity, Vol. 41, Issue 4 https://doi.org/10.1016/j.immuni.2014.10.004	journal	October 2014
Th2 Lymphoproliferative Disorder of Lat ^Y136F Mutant Mice Unfolds Independently of TCR-MHC Engagement and Is Insensitive to the Action of Foxp3 ⁺ Regulatory T Cells Wang, Ying; Kissenpfennig, Adrien; Mingueneau, Michael The Journal of Immunology, Vol. 180, Issue 3 https://doi.org/10.4049/jimmunol.180.3.1565	journal	January 2008
Gadd45β is important for perpetuating cognate and inflammatory signals in T cells Lu, Binfeng; Ferrandino, Anthony F.; Flavell, Richard A. Nature Immunology, Vol. 5, Issue 1 https://doi.org/10.1038/ni1020	journal	December 2003
Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions Chung, Yeonseok; Tanaka, Shinya; Chu, Fuliang Nature Medicine, Vol. 17, Issue 8 https://doi.org/10.1038/nm.2426	journal	July 2011
ICOS Deficiency Is Associated with a Severe Reduction of CXCR5 ⁺ CD4 Germinal Center Th Cells Bossaller, Lukas; Burger, Jan; Draeger, Ruth The Journal of Immunology, Vol. 177, Issue 7 https://doi.org/10.4049/jimmunol.177.7.4927	journal	September 2006
GILZ regulates Th17 responses and restrains IL-17-mediated skin inflammation Jones, Sarah A.; Perera, Diluptha N.; Fan, Huapeng Journal of Autoimmunity, Vol. 61 https://doi.org/10.1016/j.jaut.2015.05.010	journal	July 2015
T-cell subsets in the germinal center Ramiscal, Roybel R.; Vinuesa, Carola G. Immunological Reviews, Vol. 252, Issue 1 https://doi.org/10.1111/imr.12031	journal	February 2013
Foxp3+ follicular regulatory T cells control the germinal center response Linterman, Michelle A.; Pierson, Wim; Lee, Sau K. Nature Medicine, Vol. 17, Issue 8 https://doi.org/10.1038/nm.2425	journal	July 2011
Cytokine-secreting follicular T cells shape the antibody repertoire Reinhardt, R. Lee; Liang, Hong-Erh; Locksley, Richard M. Nature Immunology, Vol. 10, Issue 4 https://doi.org/10.1038/ni.1715	journal	March 2009
Homeostatic chemokines in development, plasticity, and functional organization of the intestinal immune system Förster, Reinhold; Pabst, Oliver; Bernhardt, Günter Seminars in Immunology, Vol. 20, Issue 3 https://doi.org/10.1016/j.smim.2008.03.001	journal	June 2008
T Follicular Helper Cell Dynamics in Germinal Centers Shulman, Z.; Gitlin, A. D.; Targ, S. Science, Vol. 341, Issue 6146 https://doi.org/10.1126/science.1241680	journal	July 2013
The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood Sage, Peter T.; Francisco, Loise M.; Carman, Christopher V. Nature Immunology, Vol. 14, Issue 2 https://doi.org/10.1038/ni.2496	journal	December 2012
Dynamic control of 1 integrin adhesion by the plexinD1-sema3E axis Choi, Y. I.; Duke-Cohan, J. S.; Chen, W. Proceedings of the National Academy of Sciences, Vol. 111, Issue 1 https://doi.org/10.1073/pnas.1314209111	journal	December 2013
The Interleukin-2-mTORc1 Kinase Axis Defines the Signaling, Differentiation, and Metabolism of T Helper 1 and Follicular B Helper T Cells Ray, John P.; Staron, Matthew M.; Shyer, Justin A. Immunity, Vol. 43, Issue 4 https://doi.org/10.1016/j.immuni.2015.08.017	journal	October 2015
Interleukin-4 Production by Follicular Helper T Cells Requires the Conserved Il4 Enhancer Hypersensitivity Site V Vijayanand, Pandurangan; Seumois, Grégory; Simpson, Laura J. Immunity, Vol. 36, Issue 2 https://doi.org/10.1016/j.immuni.2011.12.014	journal	February 2012
The Transcription Factor KLF2 Restrains CD4 + T Follicular Helper Cell Differentiation Lee, June-Yong; Skon, Cara N.; Lee, You Jeong Immunity, Vol. 42, Issue 2 https://doi.org/10.1016/j.immuni.2015.01.013	journal	February 2015
IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2 Jandl, Christoph; Liu, Sue M.; Cañete, Pablo F. Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/ncomms14647	journal	March 2017
Hemophagocytic lymphohistiocytosis in syntaxin-11–deficient mice: T-cell exhaustion limits fatal disease Kögl, Tamara; Müller, Jürgen; Jessen, Birthe Blood, Vol. 121, Issue 4 https://doi.org/10.1182/blood-2012-07-441139	journal	January 2013
Germinal Center T Follicular Helper Cell IL-4 Production Is Dependent on Signaling Lymphocytic Activation Molecule Receptor (CD150) Yusuf, Isharat; Kageyama, Robin; Monticelli, Laurel The Journal of Immunology, Vol. 185, Issue 1 https://doi.org/10.4049/jimmunol.0903505	journal	June 2010
GARP (LRRC32) is essential for the surface expression of latent TGF- on platelets and activated FOXP3+ regulatory T cells Tran, D. Q.; Andersson, J.; Wang, R. Proceedings of the National Academy of Sciences, Vol. 106, Issue 32 https://doi.org/10.1073/pnas.0901944106	journal	July 2009
Lymphoid reservoirs of antigen-specific memory T helper cells Fazilleau, Nicolas; Eisenbraun, Michael D.; Malherbe, Laurent Nature Immunology, Vol. 8, Issue 7 https://doi.org/10.1038/ni1472	journal	May 2007
The Transcriptional Repressor Bcl-6 Directs T Follicular Helper Cell Lineage Commitment Yu, Di; Rao, Sudha; Tsai, Louis M. Immunity, Vol. 31, Issue 3 https://doi.org/10.1016/j.immuni.2009.07.002	journal	September 2009
IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells Batten, Marcel; Ramamoorthi, Nandhini; Kljavin, Noelyn M. The Journal of Experimental Medicine, Vol. 207, Issue 13 https://doi.org/10.1084/jem.20100064	journal	November 2010
The small MAF transcription factors MAFF, MAFG and MAFK: Current knowledge and perspectives Kannan, Meenakshi B.; Solovieva, Vera; Blank, Volker Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. 1823, Issue 10 https://doi.org/10.1016/j.bbamcr.2012.06.012	journal	October 2012
Germinal Center B Cell and T Follicular Helper Cell Development Initiates in the Interfollicular Zone Kerfoot, Steven M.; Yaari, Gur; Patel, Jaymin R. Immunity, Vol. 34, Issue 6 https://doi.org/10.1016/j.immuni.2011.03.024	journal	June 2011
TFH cells progressively differentiate to regulate the germinal center response Weinstein, Jason S.; Herman, Edward I.; Lainez, Begoña Nature Immunology, Vol. 17, Issue 10 https://doi.org/10.1038/ni.3554	journal	August 2016
Metabolic checkpoints in activated T cells Wang, Ruoning; Green, Douglas R. Nature Immunology, Vol. 13, Issue 10 https://doi.org/10.1038/ni.2386	journal	September 2012
Critical Regulation of Early Th17 Cell Differentiation by Interleukin-1 Signaling Chung, Yeonseok; Chang, Seon Hee; Martinez, Gustavo J. Immunity, Vol. 30, Issue 4 https://doi.org/10.1016/j.immuni.2009.02.007	journal	April 2009
Bcl-6 directly represses the gene program of the glycolysis pathway Oestreich, Kenneth J.; Read, Kaitlin A.; Gilbertson, Sarah E. Nature Immunology, Vol. 15, Issue 10 https://doi.org/10.1038/ni.2985	journal	September 2014
Batf is important for IL-4 expression in T follicular helper cells Sahoo, Anupama; Alekseev, Andrei; Tanaka, Kentaro Nature Communications, Vol. 6, Issue 1 https://doi.org/10.1038/ncomms8997	journal	August 2015
Unequal Death in T Helper Cell (Th)1 and Th2 Effectors: Th1, but not Th2, Effectors Undergo Rapid Fas/FasL-mediated Apoptosis Zhang, Xiaohong; Brunner, Thomas; Carter, Laura The Journal of Experimental Medicine, Vol. 185, Issue 10 https://doi.org/10.1084/jem.185.10.1837	journal	May 1997
Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis Chang, Chih-Hao; Curtis, Jonathan D.; Maggi, Leonard B. Cell, Vol. 153, Issue 6 https://doi.org/10.1016/j.cell.2013.05.016	journal	June 2013
The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells Bauquet, Aurelie T.; Jin, Hulin; Paterson, Alison M. Nature Immunology, Vol. 10, Issue 2 https://doi.org/10.1038/ni.1690	journal	December 2008
Follicular B helper T cell activity is confined to CXCR5hiICOShi CD4 T cells and is independent of CD57 expression Rasheed, Ata-Ur; Rahn, Hans-Peter; Sallusto, Federica European Journal of Immunology, Vol. 36, Issue 7 https://doi.org/10.1002/eji.200636136	journal	July 2006
The development and fate of follicular helper T cells defined by an IL-21 reporter mouse Lüthje, Katja; Kallies, Axel; Shimohakamada, Yoko Nature Immunology, Vol. 13, Issue 5 https://doi.org/10.1038/ni.2261	journal	April 2012
T follicular regulatory cells Sage, Peter T.; Sharpe, Arlene H. Immunological Reviews, Vol. 271, Issue 1 https://doi.org/10.1111/imr.12411	journal	April 2016
Bcl6 and Blimp-1 Are Reciprocal and Antagonistic Regulators of T Follicular Helper Cell Differentiation Johnston, R. J.; Poholek, A. C.; DiToro, D. Science, Vol. 325, Issue 5943 https://doi.org/10.1126/science.1175870	journal	July 2009
Role of CXCR5 and CCR7 in Follicular Th Cell Positioning and Appearance of a Programmed Cell Death Gene-1 ^High Germinal Center-Associated Subpopulation Haynes, Nicole M.; Allen, Christopher D. C.; Lesley, Robin The Journal of Immunology, Vol. 179, Issue 8 https://doi.org/10.4049/jimmunol.179.8.5099	journal	October 2007
Interleukin-2 Inhibits Germinal Center Formation by Limiting T Follicular Helper Cell Differentiation Ballesteros-Tato, André; León, Beatriz; Graf, Beth A. Immunity, Vol. 36, Issue 5 https://doi.org/10.1016/j.immuni.2012.02.012	journal	May 2012
Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection Botta, Davide; Fuller, Michael J.; Marquez-Lago, Tatiana T. Nature Immunology, Vol. 18, Issue 11 https://doi.org/10.1038/ni.3837	journal	September 2017
Molecular and cellular insights into T cell exhaustion Wherry, E. John; Kurachi, Makoto Nature Reviews Immunology, Vol. 15, Issue 8 https://doi.org/10.1038/nri3862	journal	July 2015
Follicular B Helper T Cells Express Cxc Chemokine Receptor 5, Localize to B Cell Follicles, and Support Immunoglobulin Production Breitfeld, Dagmar; Ohl, Lars; Kremmer, Elisabeth The Journal of Experimental Medicine, Vol. 192, Issue 11 https://doi.org/10.1084/jem.192.11.1545	journal	November 2000
Identification of a secreted BMP antagonist, ectodin, integrating BMP, FGF, and SHH signals from the tooth enamel knot Laurikkala, Johanna; Kassai, Yoshiaki; Pakkasjärvi, Leila Developmental Biology, Vol. 264, Issue 1 https://doi.org/10.1016/j.ydbio.2003.08.011	journal	December 2003
Plasticity of TH17 cells in Peyer's patches is responsible for the induction of T cell–dependent IgA responses Hirota, Keiji; Turner, Jan-Eric; Villa, Matteo Nature Immunology, Vol. 14, Issue 4 https://doi.org/10.1038/ni.2552	journal	March 2013
Ephrin B1–mediated repulsion and signaling control germinal center T cell territoriality and function Lu, Peiwen; Shih, Changming; Qi, Hai Science, Vol. 356, Issue 6339 https://doi.org/10.1126/science.aai9264	journal	April 2017
Bone morphogenetic proteins inhibit CD40L/IL-21-induced Ig production in human Bcells: Differential effects of BMP-6 and BMP-7 Huse, Kanutte; Bakkebø, Maren; Oksvold, Morten P. European Journal of Immunology, Vol. 41, Issue 11 https://doi.org/10.1002/eji.201141558	journal	October 2011
The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells Ise, Wataru; Kohyama, Masako; Schraml, Barbara U. Nature Immunology, Vol. 12, Issue 6 https://doi.org/10.1038/ni.2037	journal	May 2011
Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2 Yokosuka, Tadashi; Takamatsu, Masako; Kobayashi-Imanishi, Wakana The Journal of Experimental Medicine, Vol. 209, Issue 6 https://doi.org/10.1084/jem.20112741	journal	May 2012
IL-17RA Is Essential for Optimal Localization of Follicular Th Cells in the Germinal Center Light Zone To Promote Autoantibody-Producing B Cells Ding, Yanna; Li, Jun; Wu, Qi The Journal of Immunology, Vol. 191, Issue 4 https://doi.org/10.4049/jimmunol.1300479	journal	July 2013
A Temporal Switch in the Germinal Center Determines Differential Output of Memory B and Plasma Cells Weisel, Florian J.; Zuccarino-Catania, Griselda V.; Chikina, Maria Immunity, Vol. 44, Issue 1 https://doi.org/10.1016/j.immuni.2015.12.004	journal	January 2016
Preferential Generation of Follicular B Helper T Cells from Foxp3+ T Cells in Gut Peyer's Patches Tsuji, M.; Komatsu, N.; Kawamoto, S. Science, Vol. 323, Issue 5920 https://doi.org/10.1126/science.1169152	journal	March 2009
Peyer's patches: organizing B-cell responses at the intestinal frontier Reboldi, Andrea; Cyster, Jason G. Immunological Reviews, Vol. 271, Issue 1 https://doi.org/10.1111/imr.12400	journal	April 2016
The impact of cell-bound antigen transport on mucosal tolerance induction Pabst, Oliver; Bernhardt, Günter; Förster, Reinhold Journal of Leukocyte Biology, Vol. 82, Issue 4 https://doi.org/10.1189/jlb.0307144	journal	June 2007
The 3′ Enhancer CNS2 Is a Critical Regulator of Interleukin-4-Mediated Humoral Immunity in Follicular Helper T Cells Harada, Yohsuke; Tanaka, Shinya; Motomura, Yasutaka Immunity, Vol. 36, Issue 2 https://doi.org/10.1016/j.immuni.2012.02.002	journal	February 2012
IgA production requires B cell interaction with subepithelial dendritic cells in Peyers patches Reboldi, A.; Arnon, T. I.; Rodda, L. B. Science, Vol. 352, Issue 6287 https://doi.org/10.1126/science.aaf4822	journal	May 2016
Regulated Compartmentalization of Programmed Cell Death-1 Discriminates CD4 ⁺ CD25 ⁺ Resting Regulatory T Cells from Activated T Cells Raimondi, Giorgio; Shufesky, William J.; Tokita, Daisuke The Journal of Immunology, Vol. 176, Issue 5 https://doi.org/10.4049/jimmunol.176.5.2808	journal	February 2006
Foxp3-dependent programme of regulatory T-cell differentiation Gavin, Marc A.; Rasmussen, Jeffrey P.; Fontenot, Jason D. Nature, Vol. 445, Issue 7129 https://doi.org/10.1038/nature05543	journal	January 2007

Cited By (5)

Regulation of the Germinal Center Response Stebegg, Marisa; Kumar, Saumya D.; Silva-Cayetano, Alyssa Frontiers in Immunology, Vol. 9 https://doi.org/10.3389/fimmu.2018.02469	journal	October 2018
T-Follicular Regulatory Cells: Potential Therapeutic Targets in Rheumatoid Arthritis Ding, Tingting; Niu, Hongqing; Zhao, Xiangcong Frontiers in Immunology, Vol. 10 https://doi.org/10.3389/fimmu.2019.02709	journal	November 2019
T-Follicular Regulatory Cells: Potential Therapeutic Targets in Rheumatoid Arthritis Ding, Tingting; Niu, Hongqing; Zhao, Xiangcong Frontiers in Immunology, Vol. 10 https://doi.org/10.3389/fimmu.2019.02709	journal	November 2019
Regulation of the Germinal Center Response Stebegg, Marisa; Kumar, Saumya D.; Silva-Cayetano, Alyssa Frontiers in Immunology, Vol. 9 https://doi.org/10.3389/fimmu.2018.02469	journal	October 2018
Wnt Antagonists in Hematopoietic and Immune Cell Fate: Implications for Osteoporosis Therapies Chicana, Betsabel; Donham, Cristine; Millan, Alberto J. Current Osteoporosis Reports, Vol. 17, Issue 2 https://doi.org/10.1007/s11914-019-00503-3	journal	March 2019

Similar Records

A novel mouse model for tracking the fate of CXCR5-expressing T cells

Journal Article · 2018 · Biochemical and Biophysical Research Communications · OSTI ID:23127478

Takebe, Tomo; Sakamoto, Kazuki; Higami, Yoshikazu; +1 more

CTLA-4 regulates T follicular regulatory cell differentiation and participates in intestinal damage caused by spontaneous autoimmunity

Journal Article · 2018 · Biochemical and Biophysical Research Communications · OSTI ID:23107779

Chao, Gao; Li, Xiaoli; Ji, Yahong; +5 more

Antitumor CD8 T cell responses in glioma patients are effectively suppressed by T follicular regulatory cells

Journal Article · 2021 · Experimental Cell Research · OSTI ID:23195483

Lu, Lenian; Sun, Jie; Su, Hang; +7 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES

Title: Shared and Unique Features Distinguishing Follicular T Helper and Regulatory Cells of Peripheral Lymph Node and Peyer’s Patches

Citation Formats

References (67)

Cited By (5)

Similar Records

Related Subjects