Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4.
The mannose receptor (MR) is an endocytic receptor involved in serum homeostasis and antigen presentation. Here, we identify the MR as a direct regulator of CD8(+) T-cell activity. We demonstrate that MR expression on dendritic cells (DCs) impaired T-cell cytotoxicity in vitro and in vivo. This regulatory effect of the MR was mediated by a direct interaction with CD45 on the T cell, inhibiting its phosphatase activity, which resulted in up-regulation of cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) and the induction of T-cell tolerance. Inhibition of CD45 prevented expression of B-cell lymphoma 6 (Bcl-6), a transcriptional inhibitor that directly bound the CTLA-4 promoter and regulated its activity. These data demonstrate that endocytic receptors expressed on DCs contribute to the regulation of T-cell functionality.
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
Verena
V
Schuette
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
Maria
M
Embgenbroich
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
Thomas
T
Ulas
Clinic for Orthopaedics and Trauma Surgery, University Hospital Bonn, 53127 Bonn, Germany;
Meike
M
Welz
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
Jonas
J
Schulte-Schrepping
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
Astrid M
AM
Draffehn
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
Thomas
T
Quast
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
Katharina
K
Koch
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
Melanie
M
Nehring
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
Jessica
J
König
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
Annegret
A
Zweynert
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
Frederike L
FL
Harms
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
Nancy
N
Steiner
Clinic for Orthopaedics and Trauma Surgery, University Hospital Bonn, 53127 Bonn, Germany;
Andreas
A
Limmer
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
Irmgard
I
Förster
Institute of Pathology, University of Wurzburg, 97080 Wurzburg, Germany;
Friederike
F
Berberich-Siebelt
Institute of Molecular Immunology, Technische Universität München, 81675 Munich, Germany.
Percy A
PA
Knolle
Institute of Molecular Immunology, Technische Universität München, 81675 Munich, Germany.
Dirk
D
Wohlleber
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
Waldemar
W
Kolanus
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
Marc
M
Beyer
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
Joachim L
JL
Schultze
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany; burgdorf@uni-bonn.de.
Sven
S
Burgdorf
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D037181:Lectins, C-Type / Q000235:genetics* / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000235:genetics* / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D015533:Transcriptional Activation / Q000235:genetics
D060908:CTLA-4 Antigen; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D051560:Proto-Oncogene Proteins c-bcl-6; D011956:Receptors, Cell Surface; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human
CD45; T-cell activation; endocytosis receptors; tolerance