The TNF Receptor Superfamily-NF-κB Axis Is Critical to Maintain Effector Regulatory T Cells in Lymphoid and Non-lymphoid Tissues

Ajithkumar Vasanthakumar; Yang Liao; Peggy Teh; Maria F Pascutti; Anna E Oja; Alexandra L Garnham; Renee Gloury; Jessica C Tempany; Tom Sidwell; Eloy Cuadrado; Paul Tuijnenburg; Taco W Kuijpers; Najoua Lalaoui; Lisa A Mielke; Vanessa L Bryant; Philip D Hodgkin; John Silke; Gordon K Smyth; Martijn A Nolte; Wei Shi; Axel Kallies

doi:10.1016/j.celrep.2017.08.068

The TNF Receptor Superfamily-NF-κB Axis Is Critical to Maintain Effector Regulatory T Cells in Lymphoid and Non-lymphoid Tissues

Cell Rep. 2017 Sep 19;20(12):2906-2920. doi: 10.1016/j.celrep.2017.08.068. Epub 2017 Sep 7.

Authors

Ajithkumar Vasanthakumar¹, Yang Liao², Peggy Teh³, Maria F Pascutti⁴, Anna E Oja⁴, Alexandra L Garnham², Renee Gloury⁵, Jessica C Tempany⁶, Tom Sidwell⁵, Eloy Cuadrado⁷, Paul Tuijnenburg⁸, Taco W Kuijpers⁸, Najoua Lalaoui⁹, Lisa A Mielke⁵, Vanessa L Bryant⁶, Philip D Hodgkin⁶, John Silke⁹, Gordon K Smyth¹⁰, Martijn A Nolte⁴, Wei Shi¹¹, Axel Kallies¹²

Affiliations

¹ Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Australia. Electronic address: [email protected].
² Department of Medical Biology, University of Melbourne, Melbourne, Australia; Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
³ Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Australia; Alfred Health and Western Health, Melbourne, Australia.
⁴ Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, the Netherlands.
⁵ Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Australia.
⁶ Department of Medical Biology, University of Melbourne, Melbourne, Australia; Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
⁷ Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, the Netherlands; Department of Pediatric Hematology, Immunology, and Infectious Diseases, Emma Children's Hospital, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, the Netherlands.
⁸ Department of Pediatric Hematology, Immunology, and Infectious Diseases, Emma Children's Hospital, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, the Netherlands.
⁹ Department of Medical Biology, University of Melbourne, Melbourne, Australia; Cell Signalling and Cell Death Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
¹⁰ Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; The Department of Mathematics and Statistics, University of Melbourne, Melbourne, Australia.
¹¹ Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Computing and Information Systems, University of Melbourne, Melbourne, Australia.
¹² Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. Electronic address: [email protected].

PMID: 28889989
DOI: 10.1016/j.celrep.2017.08.068

Abstract

After exiting the thymus, Foxp3⁺ regulatory T (Treg) cells undergo further differentiation in the periphery, resulting in the generation of mature, fully suppressive effector (e)Treg cells in a process dependent on TCR signaling and the transcription factor IRF4. Here, we show that tumor necrosis factor receptor superfamily (TNFRSF) signaling plays a crucial role in the development and maintenance of eTreg cells. TNFRSF signaling activated the NF-κB transcription factor RelA, which was required to maintain eTreg cells in lymphoid and non-lymphoid tissues, including RORγt⁺ Treg cells in the small intestine. In response to TNFRSF signaling, RelA regulated basic cellular processes, including cell survival and proliferation, but was dispensable for IRF4 expression or DNA binding, indicating that both pathways operated independently. Importantly, mutations in the RelA binding partner NF-κB1 compromised eTreg cells in humans, suggesting that the TNFRSF-NF-κB axis was required in a non-redundant manner to maintain eTreg cells in mice and humans.

Keywords: IRF4; NF-κB/RelA; RORγt(+) Treg cells; TCR; TNFRSF signaling; effector Treg cells; tissue Treg cells.

MeSH terms

Animals
Cell Differentiation
Cell Survival
Homeostasis
Humans
Interferon Regulatory Factors / metabolism
Intestines / cytology
Lymphoid Tissue / metabolism*
Mice
NF-kappa B / metabolism*
Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
Receptors, Tumor Necrosis Factor / metabolism*
Signal Transduction*
T-Lymphocytes, Regulatory / metabolism*
Transcription Factor RelA / metabolism

Substances

Interferon Regulatory Factors
NF-kappa B
Nuclear Receptor Subfamily 1, Group F, Member 3
Receptors, Tumor Necrosis Factor
Transcription Factor RelA
interferon regulatory factor-4