TCAIM decreases T cell priming capacity of dendritic cells by inhibiting TLR-induced Ca2+ influx and IL-2 production.
We previously showed that the T cell activation inhibitor, mitochondrial (Tcaim) is highly expressed in grafts of tolerance-developing transplant recipients and that the encoded protein is localized within mitochondria. In this study, we show that CD11c(+) dendritic cells (DCs), as main producers of TCAIM, downregulate Tcaim expression after LPS stimulation or in vivo alloantigen challenge. LPS-stimulated TCAIM-overexpressing bone marrow-derived DC (BMDCs) have a reduced capacity to induce proliferation of and cytokine expression by cocultured allogeneic T cells; this is not due to diminished upregulation of MHC or costimulatory molecules. Transcriptional profiling also revealed normal LPS-mediated upregulation of the majority of genes involved in TLR signaling. However, TCAIM BMDCs did not induce Il2 mRNA expression upon LPS stimulation in comparison with Control-BMDCs. In addition, TCAIM overexpression abolished LPS-mediated Ca(2+) influx and mitochondrial reactive oxygen species formation. Addition of IL-2 to BMDC-T cell cocultures restored the priming capacity of TCAIM BMDCs for cocultured allogeneic CD8(+) T cells. Furthermore, BMDCs of IL-2-deficient mice showed similarly abolished LPS-induced T cell priming as TCAIM-overexpressing wild type BMDCs. Thus, TCAIM interferes with TLR4 signaling in BMDCs and subsequently impairs their T cell priming capacity, which supports its role for tolerance induction.
Institute of Medical Immunology, Charite University Medicine, Berlin 13353, Germany;
Simone Z
SZ
Vogel
Institute of Medical Immunology, Charite University Medicine, Berlin 13353, Germany;
Stephan
S
Schlickeiser
Berlin Brandenburg Center for Regenerative Therapies, Charite University Medicine, Berlin 13353, Germany;
Karsten
K
Jürchott
Institute of Medical Immunology, Charite University Medicine, Berlin 13353, Germany; Berlin Brandenburg Center for Regenerative Therapies, Charite University Medicine, Berlin 13353, Germany;
Levent
L
Akyuez
Institute of Medical Immunology, Charite University Medicine, Berlin 13353, Germany;
Julia
J
Schumann
Institute of Medical Immunology, Charite University Medicine, Berlin 13353, Germany;
Christine
C
Appelt
Institute of Medical Immunology, Charite University Medicine, Berlin 13353, Germany;
Katrin
K
Vogt
Institute of Immunology, Department of Biology, Maynooth University, National University of Ireland Maynooth, County Kildare, Ireland;
Martina
M
Schröder
Department of Molecular Pathology, Institute of Pathology, Julius Maximilians University of Würzburg, Würzburg 97080, Germany; and.
Martin
M
Vaeth
Department of Molecular Pathology, Institute of Pathology, Julius Maximilians University of Würzburg, Würzburg 97080, Germany; and.
Friederike
F
Berberich-Siebelt
Institute of Virology and Immunobiology, Julius Maximilians University of Würzburg, Würzburg 97078, Germany.
Manfred B
MB
Lutz
Institute of Medical Immunology, Charite University Medicine, Berlin 13353, Germany;
Gerald
G
Grütz
Institute of Medical Immunology, Charite University Medicine, Berlin 13353, Germany; Berlin Brandenburg Center for Regenerative Therapies, Charite University Medicine, Berlin 13353, Germany; birgit.sawitzki@charite.de.
Birgit
B
Sawitzki
D000818:Animals; D051940:B7-2 Antigen / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D016000:Cluster Analysis; D003713:Dendritic Cells / Q000276:immunology*; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism*; D014184:Transplantation, Homologous
D051940:B7-2 Antigen; D022782:CCAAT-Enhancer-Binding Protein-beta; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D008070:Lipopolysaccharides; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C543717:TOAG-1 protein, mouse; D051193:Toll-Like Receptors; D002118:Calcium