Thymic regulatory T cells arise via two distinct developmental programs

David L Owen; Shawn A Mahmud; Louisa E Sjaastad; Jason B Williams; Justin A Spanier; Dimitre R Simeonov; Roland Ruscher; Weishan Huang; Irina Proekt; Corey N Miller; Can Hekim; Jonathan C Jeschke; Praful Aggarwal; Ulrich Broeckel; Rebecca S LaRue; Christine M Henzler; Maria-Luisa Alegre; Mark S Anderson; Avery August; Alexander Marson; Ye Zheng; Calvin B Williams; Michael A Farrar

doi:10.1038/s41590-018-0289-6

Thymic regulatory T cells arise via two distinct developmental programs

Nat Immunol. 2019 Feb;20(2):195-205. doi: 10.1038/s41590-018-0289-6. Epub 2019 Jan 14.

Authors

David L Owen¹, Shawn A Mahmud¹, Louisa E Sjaastad¹, Jason B Williams², Justin A Spanier³, Dimitre R Simeonov^{4

5

6}, Roland Ruscher¹, Weishan Huang^{7

8}, Irina Proekt⁵, Corey N Miller⁵, Can Hekim¹, Jonathan C Jeschke², Praful Aggarwal⁹, Ulrich Broeckel⁹, Rebecca S LaRue¹⁰, Christine M Henzler¹⁰, Maria-Luisa Alegre¹¹, Mark S Anderson^{5

12}, Avery August⁷, Alexander Marson^{4

5

12

13

14}, Ye Zheng¹⁵, Calvin B Williams², Michael A Farrar¹⁶

Affiliations

¹ Center for Immunology, Masonic Cancer Center, and the Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
² Section of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
³ Center for Immunology, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
⁴ Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA.
⁵ Diabetes Center, University of California San Francisco, San Francisco, CA, USA.
⁶ Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA.
⁷ Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
⁸ Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA.
⁹ Section of Genomic Pediatrics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
¹⁰ Supercomputing Institute for Advanced Computational Research, University of Minnesota, Minneapolis, MN, USA.
¹¹ Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL, USA.
¹² Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
¹³ Chan Zuckerberg Biohub, San Francisco, San Francisco, CA, USA.
¹⁴ Innovative Genomics Institute, University of California, Berkeley, CA, USA.
¹⁵ Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, La Jolla, CA, USA.
¹⁶ Center for Immunology, Masonic Cancer Center, and the Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA. farra005@umn.edu.

Abstract

The developmental programs that generate a broad repertoire of regulatory T cells (T_reg cells) able to respond to both self antigens and non-self antigens remain unclear. Here we found that mature T_reg cells were generated through two distinct developmental programs involving CD25⁺ T_reg cell progenitors (CD25⁺ T_regP cells) and Foxp3^lo T_reg cell progenitors (Foxp3^lo T_regP cells). CD25⁺ T_regP cells showed higher rates of apoptosis and interacted with thymic self antigens with higher affinity than did Foxp3^lo T_regP cells, and had a T cell antigen receptor repertoire and transcriptome distinct from that of Foxp3^lo T_regP cells. The development of both CD25⁺ T_regP cells and Foxp3^lo T_regP cells was controlled by distinct signaling pathways and enhancers. Transcriptomics and histocytometric data suggested that CD25⁺ T_regP cells and Foxp3^lo T_regP cells arose by coopting negative-selection programs and positive-selection programs, respectively. T_reg cells derived from CD25⁺ T_regP cells, but not those derived from Foxp3^lo T_regP cells, prevented experimental autoimmune encephalitis. Our findings indicate that T_reg cells arise through two distinct developmental programs that are both required for a comprehensive T_reg cell repertoire capable of establishing immunotolerance.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoantigens / immunology
Cell Differentiation / immunology*
Colitis / immunology
Disease Models, Animal
Encephalomyelitis, Autoimmune, Experimental / immunology*
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism
Freund's Adjuvant / administration & dosage
Freund's Adjuvant / immunology
Humans
Immune Tolerance / immunology
Interleukin-2 Receptor alpha Subunit / metabolism
Lymphoid Progenitor Cells / physiology*
Lymphoid Progenitor Cells / transplantation
Mice
Mice, Transgenic
Mycobacterium tuberculosis / immunology
Myelin-Oligodendrocyte Glycoprotein / administration & dosage
Myelin-Oligodendrocyte Glycoprotein / immunology
Peptide Fragments / administration & dosage
Peptide Fragments / immunology
Signal Transduction
Specific Pathogen-Free Organisms
T-Lymphocytes, Regulatory / physiology*
Thymus Gland / cytology
Thymus Gland / growth & development*
Thymus Gland / immunology

Substances

Autoantigens
Forkhead Transcription Factors
Foxp3 protein, mouse
Il2ra protein, mouse
Interleukin-2 Receptor alpha Subunit
Myelin-Oligodendrocyte Glycoprotein
Peptide Fragments
myelin oligodendrocyte glycoprotein (35-55)
Freund's Adjuvant

Abstract

Publication types

MeSH terms

Substances

Grants and funding