The Influence of Apoptotic Cells on the Immune Response

Introduction

The Influence of Apoptotic Cells on the Immune Response: Dendritic cells (DC) initiate immunity or tolerance in response to specific signals. While pathogen associated danger signals lead to inflammatory DC and stimulation of specific T cells, suppressive signals exposed on apoptotic cells like annexin 1 lead to a tolerogenic DC phenotype.
© Dr. Heiko Weyd

In multicellular organisms, the continuous removal of excess cells by apoptosis maintains tissue homeostasis. To preclude the release of noxious cellular content and the development of autoimmunity, dying cells are rapidly cleared by phagocytes, such as macrophages or dendritic cells (DC), which reside in peripheral tissues as sentinels of the immune system. Specific signals on the surface of apoptotic cells mediate efficient engulfment as well as suppression of immune responses against self antigens. However, aside from exposure of phosphatidylserine, apoptotic cell-related anti-inflammatory signals remain largely elusive to date. To gain insight into the immunosuppressive signals of apoptotic cells and the regulation of peripheral tolerance, we investigated the influence of apoptotic cells on antigen presenting cells of the immune system as well as the role of candidate effector molecules on the surface of apoptotic cells.

Annexin 1 on the surface of apoptotic cells suppresses DC activation

The influence of apoptotic cells on the immune response. A: Apoptotic cells suppress LPS-induced TNF-secretion by dendritic cells (DC) in a cell contact-dependent manner. B: The monoclonal antibody Nr. 5 (mAB 5) recognizes specifically apoptotic cells.
© Dr. Heiko Weyd

By raising monoclonal antibodies against the surface of apoptotic cells we identified the calcium-binding protein annexin 1 as a mediator of anti-inflammatory properties of apoptotic cells. Induction of apoptosis by CD95-stimulating antibodies, γ-irradiation or UV-irradiation led to early exposure of this cytosolic protein on the outer surface of the apoptotic membrane, where it bound to negatively charged phospholipids in a calcium-dependent manner. In vitro, purified annexin 1 mimicked the suppressive effect of apoptotic cells on Toll-like receptor (TLR)-induced DC maturation as measured by impaired upregulation of costimulatory surface molecules (CD86, MHC class II) and severely reduced pro-inflammatory cytokine release (TNF, IL-6, IL-12). Of note, inhibitory surface molecules and cytokines like PD-L1, ICOS-L, TGF-β and IL-10 were not suppressed or even induced by annexin 1. In contrast to stimulation by mature DC, stimulation by DC that were incubated with recombinant annexin 1 prior to maturation led to a significant reduction in proliferation and interferon-γ secretion by T cells, while secretion of Th2 cytokines like IL-13 and anti-inflammatory IL-10 was not affected.  

© dkfz.de

References

Linke, B., Abeler-Dörner, L., Jahndel, V., Kurz, A., Mahr, A., Pfrang, S., Linke, L., Krammer P. H., Weyd, H. (2015). The tolerogenic function of annexins on apoptotic cells is  mediated by the annexin core domain. J Immunol. 194(11)

Kuhn A, Wenzel J, Weyd H. (2014). Photosensitivity, apoptosis, and cytokines in the pathogenesis of lupus erythematosus: a critical review. Clin Rev Allergy Immunol. 47(2):148-62.

Weyd, H., Abeler-Dörner, L., Linke, B., Mahr, A., Jahndel, V., Pfrang, S., Schnölzer, M., Falk, C. S., and Krammer P. H. (2013). Annexin A1 on the surface of early apoptotic cells suppresses CD8+ T cell immunity. PLoS One 30;8(4):e62449

Abeler-Dörner, L., Rieger C.C., Berger, B., Weyd, H., Gräf, D., Pfrang, S., Tarner, I.H., Schwarting, A., Lorenz, H-M., Müller-Ladner, U., Krammer P.H. and Kuhn, A. (2013). Interferon-α Abrogates the Suppressive Effect of Apoptotic Cells on Dendritic Cells in an In Vitro Model of Systemic Lupus Erythematosus Pathogenesis. J Rheumatol. 40(10):1683-96.

to top