Annexin A1 on the surface of early apoptotic cells suppresses CD8+ T cell immunity

PLoS One. 2013 Apr 30;8(4):e62449. doi: 10.1371/journal.pone.0062449. Print 2013.

Abstract

Prevention of an immune response against self-antigens derived from apoptotic cells is essential to preclude autoimmune and chronic inflammatory diseases. Here, we describe apoptosis induced externalization of endogenous cytosolic annexin 1 initiating an anti-inflammatory effector mechanism that suppresses the immune response against antigens of apoptotic cells. Cytosolic annexin 1 rapidly translocated to the apoptotic cell surface and inhibited dendritic cell (DC) activation induced by Toll like receptors (TLR). Annexin 1-inhibited DC showed strongly reduced secretion of pro-inflammatory cytokines (e.g. TNF and IL-12) and costimulatory surface molecules (e.g. CD40 and CD86), while anti-inflammatory mediators like PD-L1 remained unchanged. T cells stimulated by such DC lacked secretion of interferon-γ (IFN-γ) and TNF but retained IL-10 secretion. In mice, annexin 1 prevented the development of inflammatory DC and suppressed the cellular immune response against the model antigen ovalbumin (OVA) expressed in apoptotic cells. Furthermore, annexin 1 on apoptotic cells compromised OVA-specific tumor vaccination and impaired rejection of an OVA-expressing tumor. Thus, our results provide a molecular mechanism for the suppressive activity of apoptotic cells on the immune response towards apoptotic cell-derived self-antigens. This process may play an important role in prevention of autoimmune diseases and of the immune response against cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A1 / analysis
  • Annexin A1 / immunology*
  • Apoptosis*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Dendritic Cells / immunology
  • Humans
  • Jurkat Cells
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Signal Transduction
  • Toll-Like Receptors / immunology

Substances

  • Annexin A1
  • Toll-Like Receptors

Grants and funding

This work was supported by the Deutsche Krebshilfe, the Helmholtz Alliance on Immunotherapy of Cancer and the Deutsche Forschungsgemeinschaft (TRR77 Projekt A3). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.