Journal Article
. 2019 Aug; 216(11):2466-2478.
doi: 10.1084/jem.20190993.

IL-2 production by self-reactive CD4 thymocytes scales regulatory T cell generation in the thymus

Saskia Hemmers 1 Michail Schizas 1 Elham Azizi 2 Stanislav Dikiy 1 Yi Zhong 1 Yongqiang Feng 1 Grégoire Altan-Bonnet 3 Alexander Y Rudensky 4 
  • PMID: 31434685
  •     35 References
  •     24 citations


Regulatory T (T reg) cells, a specialized subset of CD4+ T cells, are essential to prevent fatal autoimmunity. Expression of the T reg lineage-defining transcription factor Foxp3, and therefore their differentiation in the thymus, is dependent upon T cell receptor (TCR) and interleukin-2 (IL-2) signaling. Here, we report that the majority of IL-2-producing cells in the thymus are mature CD4 single-positive (CD4SP) thymocytes and that continuous IL-2 production sustained thymic T reg cell generation and control of systemic immune activation. Furthermore, single-cell RNA sequencing analysis of CD4 thymocyte subsets revealed that IL-2 was expressed in self-reactive CD4SP thymocytes, which also contain T reg precursor cells. Thus, our results suggest that the thymic T reg cell pool size is scaled by a key niche factor, IL-2, produced by self-reactive CD4SP thymocytes. This IL-2-dependent scaling of thymic T reg cell generation by overall self-reactivity of a mature post-selection thymic precursor pool may likely ensure adequate control of autoimmunity.

ATAC-seq: A Method for Assaying Chromatin Accessibility Genome-Wide.
Jason D Buenrostro, Beijing Wu, Howard Y Chang, William J Greenleaf.
Curr Protoc Mol Biol, 2015 Jan 07; 109. PMID: 25559105    Free PMC article.
Highly Cited.
Thymic regulatory T cell niche size is dictated by limiting IL-2 from antigen-bearing dendritic cells and feedback competition.
Brian M Weist, Nadia Kurd, +2 authors, Ellen A Robey.
Nat Immunol, 2015 May 06; 16(6). PMID: 25939026    Free PMC article.
CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production.
A M Thornton, E M Shevach.
J Exp Med, 1998 Jul 22; 188(2). PMID: 9670041    Free PMC article.
Highly Cited.
Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire.
Matthew A Burchill, Jianying Yang, +7 authors, Michael A Farrar.
Immunity, 2008 Jan 18; 28(1). PMID: 18199418    Free PMC article.
Highly Cited.
T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse.
Amy E Moran, Keli L Holzapfel, +4 authors, Kristin A Hogquist.
J Exp Med, 2011 May 25; 208(6). PMID: 21606508    Free PMC article.
Highly Cited.
Differentiation of regulatory Foxp3+ T cells in the thymic cortex.
Adrian Liston, Katherine M Nutsch, +4 authors, Alexander Y Rudensky.
Proc Natl Acad Sci U S A, 2008 Aug 13; 105(33). PMID: 18695219    Free PMC article.
Highly Cited.
Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling.
Louise M D'Cruz, Ludger Klein.
Nat Immunol, 2005 Oct 18; 6(11). PMID: 16227983
Highly Cited.
Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease.
Katharina Lahl, Christoph Loddenkemper, +7 authors, Tim Sparwasser.
J Exp Med, 2007 Jan 04; 204(1). PMID: 17200412    Free PMC article.
Highly Cited.
Ontogeny and localization of the cells produce IL-2 in healthy animals.
Mutsumi Yamamoto, Yoichi Seki, +6 authors, Makio Iwashima.
Cytokine, 2013 Jan 22; 61(3). PMID: 23332616    Free PMC article.
SCANPY: large-scale single-cell gene expression data analysis.
F Alexander Wolf, Philipp Angerer, Fabian J Theis.
Genome Biol, 2018 Feb 08; 19(1). PMID: 29409532    Free PMC article.
Highly Cited.
Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells.
Fan Pan, Hong Yu, +11 authors, Drew M Pardoll.
Science, 2009 Aug 22; 325(5944). PMID: 19696312    Free PMC article.
Highly Cited.
A two-step process for thymic regulatory T cell development.
Chan-Wang Joaquim Lio, Chyi-Song Hsieh.
Immunity, 2008 Jan 18; 28(1). PMID: 18199417    Free PMC article.
Highly Cited.
IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells.
Matthew A Burchill, Jianying Yang, +2 authors, Michael A Farrar.
J Immunol, 2006 Dec 22; 178(1). PMID: 17182565
Highly Cited.
Recovering Gene Interactions from Single-Cell Data Using Data Diffusion.
David van Dijk, Roshan Sharma, +12 authors, Dana Pe'er.
Cell, 2018 Jul 03; 174(3). PMID: 29961576    Free PMC article.
Highly Cited.
Identification of Cellular Sources of IL-2 Needed for Regulatory T Cell Development and Homeostasis.
David L Owen, Shawn A Mahmud, +4 authors, Michael A Farrar.
J Immunol, 2018 May 08; 200(12). PMID: 29728511    Free PMC article.
A broad range of self-reactivity drives thymic regulatory T cell selection to limit responses to self.
Hyang-Mi Lee, Jhoanne L Bautista, +2 authors, Chyi-Song Hsieh.
Immunity, 2012 Aug 28; 37(3). PMID: 22921379    Free PMC article.
Highly Cited.
Geometric diffusions as a tool for harmonic analysis and structure definition of data: diffusion maps.
R R Coifman, S Lafon, +4 authors, S W Zucker.
Proc Natl Acad Sci U S A, 2005 May 19; 102(21). PMID: 15899970    Free PMC article.
Highly Cited.
4-1BB Signaling in Conventional T Cells Drives IL-2 Production That Overcomes CD4+CD25+FoxP3+ T Regulatory Cell Suppression.
Hampartsoum B Barsoumian, Esma S Yolcu, Haval Shirwan.
PLoS One, 2016 Apr 07; 11(4). PMID: 27049955    Free PMC article.
Data-Driven Phenotypic Dissection of AML Reveals Progenitor-like Cells that Correlate with Prognosis.
Jacob H Levine, Erin F Simonds, +13 authors, Garry P Nolan.
Cell, 2015 Jun 23; 162(1). PMID: 26095251    Free PMC article.
Highly Cited.
Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position.
Jason D Buenrostro, Paul G Giresi, +2 authors, William J Greenleaf.
Nat Methods, 2013 Oct 08; 10(12). PMID: 24097267    Free PMC article.
Highly Cited.
Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
Aravind Subramanian, Pablo Tamayo, +8 authors, Jill P Mesirov.
Proc Natl Acad Sci U S A, 2005 Oct 04; 102(43). PMID: 16199517    Free PMC article.
Highly Cited.
Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice.
Jeong M Kim, Jeffrey P Rasmussen, Alexander Y Rudensky.
Nat Immunol, 2006 Dec 01; 8(2). PMID: 17136045
Highly Cited.
Model-based analysis of ChIP-Seq (MACS).
Yong Zhang, Tao Liu, +8 authors, X Shirley Liu.
Genome Biol, 2008 Sep 19; 9(9). PMID: 18798982    Free PMC article.
Highly Cited.
Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation.
M Asano, M Toda, N Sakaguchi, S Sakaguchi.
J Exp Med, 1996 Aug 01; 184(2). PMID: 8760792    Free PMC article.
Highly Cited.
Late stages of T cell maturation in the thymus involve NF-κB and tonic type I interferon signaling.
Yan Xing, Xiaodan Wang, Stephen C Jameson, Kristin A Hogquist.
Nat Immunol, 2016 Apr 05; 17(5). PMID: 27043411    Free PMC article.
Highly Cited.
Thymic regulatory T cells arise via two distinct developmental programs.
David L Owen, Shawn A Mahmud, +20 authors, Michael A Farrar.
Nat Immunol, 2019 Jan 16; 20(2). PMID: 30643267    Free PMC article.
Highly Cited.
STAR: ultrafast universal RNA-seq aligner.
Alexander Dobin, Carrie A Davis, +6 authors, Thomas R Gingeras.
Bioinformatics, 2012 Oct 30; 29(1). PMID: 23104886    Free PMC article.
Highly Cited.
Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR.
David Zemmour, Rapolas Zilionis, +3 authors, Christophe Benoist.
Nat Immunol, 2018 Feb 13; 19(3). PMID: 29434354    Free PMC article.
Highly Cited.
The V beta-specific superantigen staphylococcal enterotoxin B: stimulation of mature T cells and clonal deletion in neonatal mice.
J White, A Herman, +3 authors, P Marrack.
Cell, 1989 Jan 13; 56(1). PMID: 2521300
Highly Cited.
Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.
Mehrdad Matloubian, Charles G Lo, +6 authors, Jason G Cyster.
Nature, 2004 Jan 23; 427(6972). PMID: 14737169
Highly Cited.
Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.
S Sakaguchi, N Sakaguchi, +2 authors, M Toda.
J Immunol, 1995 Aug 01; 155(3). PMID: 7636184
Highly Cited.
An essential role for the IL-2 receptor in Treg cell function.
Takatoshi Chinen, Arun K Kannan, +7 authors, Alexander Y Rudensky.
Nat Immunol, 2016 Oct 21; 17(11). PMID: 27595233    Free PMC article.
Highly Cited.
A function for interleukin 2 in Foxp3-expressing regulatory T cells.
Jason D Fontenot, Jeffrey P Rasmussen, Marc A Gavin, Alexander Y Rudensky.
Nat Immunol, 2005 Oct 18; 6(11). PMID: 16227984
Highly Cited.
Conditional IL-2 Gene Deletion: Consequences for T Cell Proliferation.
Zoran Popmihajlov, Dong Xu, +2 authors, Kendall A Smith.
Front Immunol, 2012 May 17; 3. PMID: 22590468    Free PMC article.
Regulatory T cell lineage specification by the forkhead transcription factor foxp3.
Jason D Fontenot, Jeffrey P Rasmussen, +3 authors, Alexander Y Rudensky.
Immunity, 2005 Mar 23; 22(3). PMID: 15780990
Highly Cited.
Regulatory T Cells in Severe Persistent Asthma in the Era of Monoclonal Antibodies Target Therapies.
L Bergantini, P Cameli, +7 authors, E Bargagli.
Inflammation, 2019 Dec 20; 43(2). PMID: 31853715
CD4+ teff cell heterogeneity: the perspective from single-cell transcriptomics.
David Zemmour, Evgeny Kiner, Christophe Benoist.
Curr Opin Immunol, 2020 Apr 08; 63. PMID: 32259715    Free PMC article.
Epigenetic conversion of conventional T cells into regulatory T cells by CD28 signal deprivation.
Norihisa Mikami, Ryoji Kawakami, +3 authors, Shimon Sakaguchi.
Proc Natl Acad Sci U S A, 2020 May 18; 117(22). PMID: 32414925    Free PMC article.
A role for cell-autocrine interleukin-2 in regulatory T-cell homeostasis.
Amanpreet Singh Chawla, Jasneet Kaur Khalsa, +6 authors, Satyajit Rath.
Immunology, 2020 Mar 19; 160(3). PMID: 32187647    Free PMC article.
Aging affects responsiveness of peripheral blood mononuclear cells to immunosuppression of periodontal ligament stem cells.
Xiaoyu Li, Bowen Zhang, +4 authors, Fulan Wei.
J Int Med Res, 2020 Jul 15; 48(7). PMID: 32663414    Free PMC article.
Impact of Aging on the Phenotype of Invariant Natural Killer T Cells in Mouse Thymus.
Georgia Papadogianni, Inga Ravens, +2 authors, Hristo Georgiev.
Front Immunol, 2020 Nov 17; 11. PMID: 33193368    Free PMC article.
High-Dimensional Data Analysis Algorithms Yield Comparable Results for Mass Cytometry and Spectral Flow Cytometry Data.
Laura Ferrer-Font, Johannes U Mayer, +3 authors, Kylie M Price.
Cytometry A, 2020 Apr 16; 97(8). PMID: 32293794    Free PMC article.
The thymus medulla and its control of αβT cell development.
Emilie J Cosway, Kieran D James, +2 authors, Andrea J White.
Semin Immunopathol, 2020 Dec 12; 43(1). PMID: 33306154    Free PMC article.
Efficient IL-2R signaling differentially affects the stability, function, and composition of the regulatory T-cell pool.
Marc Permanyer, Berislav Bošnjak, +10 authors, Reinhold Förster.
Cell Mol Immunol, 2021 Jan 08; 18(2). PMID: 33408345    Free PMC article.
Thymic origins of autoimmunity-lessons from inborn errors of immunity.
Rosa Bacchetta, Kenneth Weinberg.
Semin Immunopathol, 2021 Feb 04; 43(1). PMID: 33532929    Free PMC article.
Regulatory T Cell Heterogeneity in the Thymus: Impact on Their Functional Activities.
Jérémy C Santamaria, Alexia Borelli, Magali Irla.
Front Immunol, 2021 Mar 02; 12. PMID: 33643324    Free PMC article.
Follistatin-like 1 deficiency impairs T cell development to promote lung metastasis of triple negative breast cancer.
Jie Ma, Ying Yang, +5 authors, Yan Gao.
Aging (Albany NY), 2021 Feb 28; 13(5). PMID: 33639614    Free PMC article.
Harnessing Tolerogenic Histone Peptide Epitopes From Nucleosomes for Selective Down-Regulation of Pathogenic Autoimmune Response in Lupus (Past, Present, and Future).
Syamal K Datta.
Front Immunol, 2021 May 04; 12. PMID: 33936042    Free PMC article.
The Timing and Abundance of IL-2Rβ (CD122) Expression Control Thymic iNKT Cell Generation and NKT1 Subset Differentiation.
Hee Yeun Won, Hye Kyung Kim, +3 authors, Jung-Hyun Park.
Front Immunol, 2021 Jun 01; 12. PMID: 34054809    Free PMC article.
Wan-Nian-Qing, a Herbal Composite Prescription, Suppresses the Progression of Liver Cancer in Mice by Regulating Immune Response.
Xinrui Zhang, Xin Liu, +5 authors, Ye Qiu.
Front Oncol, 2021 Jul 27; 11. PMID: 34307161    Free PMC article.
A distal Foxp3 enhancer enables interleukin-2 dependent thymic Treg cell lineage commitment for robust immune tolerance.
Stanislav Dikiy, Jun Li, +10 authors, Yongqiang Feng.
Immunity, 2021 Apr 11; 54(5). PMID: 33838102    Free PMC article.
Phenotypic and Functional Diversity in Regulatory T Cells.
Louisa E Sjaastad, David L Owen, Sean I Tracy, Michael A Farrar.
Front Cell Dev Biol, 2021 Oct 12; 9. PMID: 34631704    Free PMC article.
A novel multi-biomarker combination predicting relapse from long-term remission after discontinuation of biological drugs in rheumatoid arthritis.
Katsuya Nagatani, Eiji Sakashita, Hitoshi Endo, Seiji Minota.
Sci Rep, 2021 Oct 23; 11(1). PMID: 34675298    Free PMC article.
Enhanced IL-2 in early life limits the development of TFH and protective antiviral immunity.
Chloe J Pyle, Lucia Labeur-Iurman, +4 authors, James A Harker.
J Exp Med, 2021 Oct 20; 218(12). PMID: 34665220    Free PMC article.
Cyclophosphamide enhances the antitumor potency of GITR engagement by increasing oligoclonal cytotoxic T cell fitness.
Daniel Hirschhorn, Allison Betof Warner, +11 authors, Jedd D Wolchok.
JCI Insight, 2021 Oct 23; 6(20). PMID: 34676831    Free PMC article.
An Integrated Epigenomic and Transcriptomic Map of Mouse and Human αβ T Cell Development.
Laura B Chopp, Vishaka Gopalan, +11 authors, Rémy Bosselut.
Immunity, 2020 Nov 27; 53(6). PMID: 33242395    Free PMC article.
Regulatory T cell function in autoimmune disease.
Anandi Rajendeeran, Klaus Tenbrock.
J Transl Autoimmun, 2022 Jan 11; 4. PMID: 35005594    Free PMC article.
Stem-like intestinal Th17 cells give rise to pathogenic effector T cells during autoimmunity.
Alexandra Schnell, Linglin Huang, +13 authors, Vijay K Kuchroo.
Cell, 2021 Dec 08; 184(26). PMID: 34875227    Free PMC article.
Role of Cytokines in Thymic Regulatory T Cell Generation: Overview and Updates.
Mei Tang, Fuya Jia, +3 authors, Dunfang Zhang.
Front Immunol, 2022 Apr 19; 13. PMID: 35432378    Free PMC article.