Poster Presentation Australasian Society for Immunology Annual Scientific Meeting 2014

TAM receptors are a novel regulatory pathway on human plasmacytoid dendritic cells modulating survival, activation and cytokine secretion (#286)

Christian Bryant 1 2 3 4 , Georgina Clark 1 2 , Michael Papadimitrious 1 2 , Elizabeth Newman 4 , Ilona Cunningham 4 , John Gibson 3 , Ross Brown 3 , Douglas Joshua 3 , Derek Hart 1 2 , Phillip Fromm 1 2
  1. The ANZAC Research Institute, Sydney, NSW, Australia
  2. The University of Sydney, Sydney, NSW, Australia
  3. The Department of Haematology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
  4. The Department of Haematology, Concord Repatriation and General Hospital, Sydney, NSW, Australia

The ability of plasmacytoid dendritic cells (pDC) to sense exogenous genetic material is critical for the defence against viruses. Autologous pDC responses to DNA are implicated in the pathology of psoriasis and SLE, but the pathways which regulate this are incompletely understood. The TAM receptors are a family of three tyrosine kinase receptors; AXL, Mer and Tyro3, which are known to regulate myeloid DC responses, however their role in modulating pDC function is unknown.

Flow cytometry analysis of TAM receptor expression on peripheral blood pDC showed no expression of Tyro3, homogeneous expression of Mer and expression of AXL in a small subset of CD2hi pDC. Stimulation with TLR7 and TLR9 ligands resulted in modest up regulation of AXL, whilst Mer and Tyro3 remained unchanged. Gas6, the well characterised ligand for the TAM receptors, induces the migration of AXL+ monocyte-derived DC1 but induced little migration of pDC. However Gas6 had profound effects on pDC survival, rescuing them from apoptosis during serum starvation, and adding significantly to the effects of IL-3.

The effect of Gas6 on the secretion of IFN-α in response to TLR9 ligand CpG-2216 was analysed. Strikingly, Gas6 suppressed IFN-α secretion in response to CpG-2216 in a dose dependent fashion. Despite this, Gas6 did not suppress the CpG-induced up-regulation of the co-stimulatory molecules CD80, CD86, CD83 or PD-L1, indeed, when present alone, it induced their partial up-regulation.

AXL and Mer are expressed on pDC and Gas6 modulates their function, decreasing the secretion of IFN-α, promoting survival and inducing partial activation. Increased expression of Mer in pDC has been recently reported in SLE2. These studies revealed a new regulatory feedback loop that may be a potential therapeutic target.

  1. Scutera, S., et al., Survival and migration of human dendritic cells are regulated by an IFN-alpha-inducible Axl/Gas6 pathway. J Immunol, 2009. 183(5): p. 3004-13.
  2. Hilliard, B.A., et al., Increased expression of Mer tyrosine kinase in circulating dendritic cells and monocytes of lupus patients: correlations with plasma interferon activity and steroid therapy. Arthritis Res Ther, 2014. 16(2): p. R76.