The tolerogenic function of annexins on apoptotic cells is mediated by the annexin core domain.
Immunological tolerance is constantly being maintained in the periphery by dendritic cells processing material from apoptotic cells (ACs) in the steady-state. Although research has focused on the uptake of ACs by phagocytes, tolerogenic signals exposed by the ACs are much less well defined. In this article, we show that the annexin (Anx) family members AnxA5 and AnxA13 translocate to the surface of ACs to function as redundant tolerogenic signals in vitro and in vivo. Exposure of bone marrow-derived dendritic cells to AnxA5 or AnxA13 in vitro resulted in the inhibition of both proinflammatory cytokine secretion and the upregulation of costimulatory molecules upon TLR stimulation. The highly conserved Anx core domain was sufficient to mediate these effects, whereas recognition by N-formyl peptide receptor family members was dispensable. In vivo, coinjection of OVA-expressing and Anx-expressing ACs prevented induction of Ag-specific CD8(+) T cells. Moreover, mice immunized with Anx-expressing ACs became refractory to an antigenic challenge. These results suggest that several Anxs contribute to AC-induced suppression of dendritic cell activation. Therefore, manipulating Anx-mediated immunosuppression may prove beneficial for patients with cancer or autoimmune diseases and chronic inflammatory disorders.
Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany.
Björn
B
Linke
Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany.
Lucie
L
Abeler-Dörner
Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany.
Veronika
V
Jahndel
Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany.
Alexandra
A
Kurz
Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany.
Andrea
A
Mahr
Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany.
Sandra
S
Pfrang
Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany.
Linda
L
Linke
Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany h.weyd@dkfz.de p.krammer@dkfz.de.
Peter H
PH
Krammer
Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany h.weyd@dkfz.de p.krammer@dkfz.de.
Heiko
H
Weyd
D000818:Animals; D017305:Annexin A1 / Q000235:genetics; D017304:Annexin A5 / Q000276:immunology* / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology; D010586:Phagocytes / Q000276:immunology; D017434:Protein Structure, Tertiary; D044042:Receptors, Formyl Peptide / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology
D017305:Annexin A1; D017304:Annexin A5; D016207:Cytokines; D044042:Receptors, Formyl Peptide; D051193:Toll-Like Receptors; C573274:annexin A1, mouse