Transcription factors early growth response gene (Egr) 2 and 3 control inflammatory responses of tolerant T cells

• Published in: Immunity, Inflammation and Disease Vol. 6; no. 2; pp. 221 - 233
• Main Authors: Omodho, Becky, Miao, Tizong, Symonds, Alistair L.J., Singh, Randeep, Li, Suling, Wang, Ping
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.06.2018; John Wiley and Sons Inc
• Subjects: Animals; Antigens; Antigens, CD - immunology; Antigens, CD - metabolism; Antigens, Differentiation, T-Lymphocyte - immunology; Antigens, Differentiation, T-Lymphocyte - metabolism; Autoantigens - immunology; Autoimmune diseases; Bone Marrow Transplantation; CD2 Antigens - immunology; CD2 Antigens - metabolism; Cell cycle; Cell growth; Cell Proliferation; Cloning; Cytokines; Disease Models, Animal; Early Growth Response Protein 2 - genetics; Early Growth Response Protein 2 - immunology; Early Growth Response Protein 2 - metabolism; Early Growth Response Protein 3 - genetics; Early Growth Response Protein 3 - immunology; Early Growth Response Protein 3 - metabolism; Egr2; Enterotoxins - administration & dosage; Enterotoxins - immunology; Experiments; Flow cytometry; Gene Expression Regulation - genetics; Gene Expression Regulation - immunology; Gene Knock-In Techniques; Humans; Hyaluronan Receptors - immunology; Hyaluronan Receptors - metabolism; Immune Tolerance - genetics; Immunoglobulins; Inflammation - immunology; Interleukin-2 - immunology; Interleukin-2 - metabolism; Lectins, C-Type - immunology; Lectins, C-Type - metabolism; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Lymphocytes; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; Original Research; Signal Transduction - genetics; Signal Transduction - immunology; T cell receptors; T cells; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; tolerance; Transcription factors; Transplantation Chimera - immunology; United Kingdom > UK; T cells; Egr2; tolerance
• ISSN: 2050-4527; 2050-4527
• DOI: 10.1002/iid3.210

Introduction Impaired proliferation and production of IL2 are the hallmarks of experimental T cell tolerance. However, in most autoimmune diseases, auto‐reactive T cells do not display hyper proliferation, but inflammatory phenotypes. Methods We have now demonstrated that the transcription factors Egr2 and 3 are important for the control of inflammatory cytokine production by tolerant T cells, but not for tolerance induction. Results In the absence of Egr2 and 3, T cell tolerance, as measured by impaired proliferation and production of IL2, can still be induced, but tolerant T cells produced high levels of inflammatory cytokines. Egr2 and 3 regulate expression of differentiation repressors and directly inhibit T‐bet function in T cells. Indeed, decreased expression of differentiation repressors, such as Id3 and Tcf1, and increased expression of inflammatory transcription factors, such as RORγt and Bhlhe40 were found in Egr2/3 deficient T cells under tolerogenic conditions. In addition, T‐bet was co‐expressed with Egr2 in tolerant T cells and Egr2/3 defects leads to production of high levels of IFNγ in tolerant T cells. Conclusions Our findings demonstrated that despite impaired proliferation and IL2 production, tolerant T cells can display inflammatory responses in response to antigen stimulation and this is controlled at least partly by Egr2 and 3. Impaired proliferation and production of IL2 are the hallmarks of experimental T cell tolerance. However, in most autoimmune diseases, auto‐reactive T cells do not display hyperproliferation, but inflammatory phenotypes. We have now demonstrated that the transcription factors Egr2 and 3 are important for the control of inflammatory cytokine production by tolerant T cells, but not for tolerance induction.