Dynamic adoption of anergy by antigen-exhausted CD4+ T cells
Anne Trefzer,
Pallavi Kadam,
Shu-Hung Wang,
Stefanie Pennavaria,
Benedikt Lober,
Batuhan Akçabozan,
Jan Kranich,
Thomas Brocker,
Naoko Nakano,
Martin Irmler,
Johannes Beckers,
Tobias Straub,
Reinhard Obst
Affiliations
Anne Trefzer
Institute for Immunology, Biomedical Center, Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
Pallavi Kadam
Institute for Immunology, Biomedical Center, Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
Shu-Hung Wang
Institute for Immunology, Biomedical Center, Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
Stefanie Pennavaria
Institute for Immunology, Biomedical Center, Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
Benedikt Lober
Institute for Immunology, Biomedical Center, Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
Batuhan Akçabozan
Institute for Immunology, Biomedical Center, Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
Jan Kranich
Institute for Immunology, Biomedical Center, Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
Thomas Brocker
Institute for Immunology, Biomedical Center, Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
Naoko Nakano
Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan
Martin Irmler
Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, 85764 Neuherberg, Germany
Johannes Beckers
Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, 85764 Neuherberg, Germany; Chair of Experimental Genetics, Technische Universität München, 85354 Freising, Germany; German Center for Diabetes Research (DZD e. V.), Neuherberg, Germany
Tobias Straub
Bioinformatics Core Facility, Biomedical Center, Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
Reinhard Obst
Institute for Immunology, Biomedical Center, Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany; Corresponding author
Summary: Exhausted immune responses to chronic diseases represent a major challenge to global health. We study CD4+ T cells in a mouse model with regulatable antigen presentation. When the cells are driven through the effector phase and are then exposed to different levels of persistent antigen, they lose their T helper 1 (Th1) functions, upregulate exhaustion markers, resemble naturally anergic cells, and modulate their MAPK, mTORC1, and Ca2+/calcineurin signaling pathways with increasing dose and time. They also become unable to help B cells and, at the highest dose, undergo apoptosis. Transcriptomic analyses show the dynamic adjustment of gene expression and the accumulation of T cell receptor (TCR) signals over a period of weeks. Upon antigen removal, the cells recover their functionality while losing exhaustion and anergy markers. Our data suggest an adjustable response of CD4+ T cells to different levels of persisting antigen and contribute to a better understanding of chronic disease.
