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
Affiliations
Ajithkumar Vasanthakumar
Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
Yang Liao
Department of Medical Biology, University of Melbourne, Melbourne, Australia
Peggy Teh
Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
Maria F. Pascutti
Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, the Netherlands
Anna E. Oja
Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, the Netherlands
Alexandra L. Garnham
Department of Medical Biology, University of Melbourne, Melbourne, Australia
Renee Gloury
Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
Jessica C. Tempany
Department of Medical Biology, University of Melbourne, Melbourne, Australia
Tom Sidwell
Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
Eloy Cuadrado
Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, the Netherlands
Paul Tuijnenburg
Department of Pediatric Hematology, Immunology, and Infectious Diseases, Emma Children’s Hospital, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, the Netherlands
Taco W. Kuijpers
Department of Pediatric Hematology, Immunology, and Infectious Diseases, Emma Children’s Hospital, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, the Netherlands
Najoua Lalaoui
Department of Medical Biology, University of Melbourne, Melbourne, Australia
Lisa A. Mielke
Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
Vanessa L. Bryant
Department of Medical Biology, University of Melbourne, Melbourne, Australia
Philip D. Hodgkin
Department of Medical Biology, University of Melbourne, Melbourne, Australia
John Silke
Department of Medical Biology, University of Melbourne, Melbourne, Australia
Gordon K. Smyth
Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
Martijn A. Nolte
Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, the Netherlands
Wei Shi
Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
Axel Kallies
Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
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.
