Continuous T Cell Receptor Signals Maintain a Functional Regulatory T Cell Pool

• Published in: Immunity (Cambridge, Mass.) Vol. 41; no. 5; pp. 722 - 736
• Main Authors: Vahl, J. Christoph, Drees, Christoph, Heger, Klaus, Heink, Sylvia, Fischer, Julius C., Nedjic, Jelena, Ohkura, Naganari, Morikawa, Hiromasa, Poeck, Hendrik, Schallenberg, Sonja, Rieß, David, Hein, Marco Y., Buch, Thorsten, Polic, Bojan, Schönle, Anne, Zeiser, Robert, Schmitt-Gräff, Annette, Kretschmer, Karsten, Klein, Ludger, Korn, Thomas, Sakaguchi, Shimon, Schmidt-Supprian, Marc
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.11.2014; Elsevier Limited
• Subjects: Animals; Autoimmunity - immunology; Cell Differentiation - immunology; Cell Lineage - immunology; DNA Methylation - immunology; DNA-Binding Proteins - genetics; Experiments; Forkhead Transcription Factors - biosynthesis; Forkhead Transcription Factors - genetics; Gene expression; Homeostasis; Immune system; Inflammation - immunology; Interferon Regulatory Factors - biosynthesis; Lymphatic system; Lymphocytes; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiprotein Complexes - metabolism; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - immunology; Signal Transduction - immunology; Spleen; T cell receptors; T-Lymphocytes, Regulatory - immunology; Thymocytes - cytology; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2014.10.012

Regulatory T (Treg) cells maintain immune homeostasis and prevent inflammatory and autoimmune responses. During development, thymocytes bearing a moderately self-reactive T cell receptor (TCR) can be selected to become Treg cells. Several observations suggest that also in the periphery mature Treg cells continuously receive self-reactive TCR signals. However, the importance of this inherent autoreactivity for Treg cell biology remains poorly defined. To address this open question, we genetically ablated the TCR of mature Treg cells in vivo. These experiments revealed that TCR-induced Treg lineage-defining Foxp3 expression and gene hypomethylation were uncoupled from TCR input in mature Treg cells. However, Treg cell homeostasis, cell-type-specific gene expression and suppressive function critically depend on continuous triggering of their TCR. •Foxp3 expression and gene-specific hypomethylation are unaffected by TCR ablation•TCR expression is critical for effector Treg cell differentiation and maintenance•The homeostatic proliferation of Treg cells depends on TCR signals•TCR ablation impairs the functional abilities of Treg cells The importance of T cell receptor (TCR) for mature regulatory T cell pool size and lineage identity is not well understood. Vahl and colleagues show that TCR signals are dispensable for Foxp3 expression, yet effector differentiation and function of regulatory T cells critically depend on continuous signaling through the TCR.