Poster Presentation Australasian Society for Immunology Annual Scientific Meeting 2014

Variable resistance to glucocorticoids reveals distinct human and murine plasmacytoid dendritic cell subsets (#287)

Christian E Bryant 1 2 3 4 , Fiona Kupresanin 1 3 , Georgina Clark 1 2 , Elizabeth Newman 4 , Cunningham Ilona 4 , Kenneth Bradstock 5 , Ross Brown 3 , John Gibson 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
  5. The Department of Haematology, Westmead Hospital, Sydney, NSW, Australia

Plasmacytoid dendritic cells (pDC) sense viral threats and produce interferon alpha (IFN-α), however aberrant or excessive IFN-α production can be deleterious, therefore mechanisms, which limit pDC responses, are required. Glucocorticoids (GC) are a key endogenous factor which regulates pDC survival to maintain immune homeostasis1. We recently described two functionally distinct human pDC subsets that respond differently under conditions of physiological stress.

Using unsupervised SPADE cluster analysis2 we have identified two distinct subsets of human pDC differentiated by their expression of the cell adhesion molecule CD2. The CD2hi and CD2low pDC have differences in phenotype, migration, cytokine secretion and T cell stimulatory capacity. However the most striking functional difference is an intrinsic survival advantage of CD2hi pDC over CD2low pDC during physiological and pharmacological stress.

CD2 cross-linking both the CD2hi and CD2low pDC induced calcium influx and promoted survival suggesting a role in pDC-stromal interactions. The CD2hi pDC had markedly increased levels of BCL-2 transcript and protein and this was associated with resistance to glucocorticoid-induced apoptosis. This explains the marked proportional enrichment of CD2hi pDC in patients receiving glucocorticoids. A CD2hi pDC subset was also identified in mouse spleens and bone marrow and had high BCL-2 expression, suggesting pDC subsets are conserved between the species.

We appear to have discovered a biological mechanism for limiting the pDC stress response. The predominant CD2low pDC population is controlled by the surge in endogenous GC and other stress mediators which accompany acute illness. The resistant CD2hi pDC population ensures that innate and adaptive immunity continues. The next challenge is to establish the ontology of these two pDC subsets. 

  1. Lepelletier, Y., et al., Toll-like receptor control of glucocorticoid-induced apoptosis in human plasmacytoid predendritic cells (pDCs). Blood, 2010. 116(18): p. 3389-97.
  2. Kotecha, N., P.O. Krutzik, and J.M. Irish, Web-based analysis and publication of flow cytometry experiments. Curr Protoc Cytom, 2010. Chapter 10: p. Unit10 17.