Id2 represses E2A-mediated activation of IL-10 expression in T cells.
Interleukin-10 (IL-10) is a key immunoregulatory cytokine that functions to prevent inflammatory and autoimmune diseases. Despite the critical role for IL-10 produced by effector CD8(+) T cells during pathogen infection and autoimmunity, the mechanisms regulating its production are poorly understood. We show that loss of the inhibitor of DNA binding 2 (Id2) in T cells resulted in aberrant IL-10 expression in vitro and in vivo during influenza virus infection and in a model of acute graft-versus-host disease (GVHD). Furthermore, IL-10 overproduction substantially reduced the immunopathology associated with GVHD. We demonstrate that Id2 acts to repress the E2A-mediated trans-activation of the Il10 locus. Collectively, our findings uncover a key regulatory role of Id2 during effector T cell differentiation necessary to limit IL-10 production by activated T cells and minimize their suppressive activity during the effector phase of disease control.
Division of Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Australia;
Frederick
F
Masson
Peter MacCallum Cancer Centre, Melbourne, Australia; and.
Margherita
M
Ghisi
Division of Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Australia;
Joanna R
JR
Groom
Division of Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Australia;
Axel
A
Kallies
Division of Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Australia;
Cyril
C
Seillet
Peter MacCallum Cancer Centre, Melbourne, Australia; and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
Ricky W
RW
Johnstone
Division of Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Australia;
Stephen L
SL
Nutt
Division of Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Australia;
Gabrielle T
GT
Belz
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001853:Bone Marrow / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D056426:Genetic Loci; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D051797:Inhibitor of Differentiation Protein 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D016176:T-Lymphocyte Subsets / Q000378:metabolism*; D015533:Transcriptional Activation
D051792:Basic Helix-Loop-Helix Proteins; D051797:Inhibitor of Differentiation Protein 2; D016753:Interleukin-10; C075668:Tcf3 protein, mouse