The absence of invariant Natural Killer T cells (iNKT cells) in mice infected with Influenza A virus (flu) has previously been shown to augment the expansion of Myeloid-derived suppressor cells (MDSCs), a bone marrow derived population that powerfully suppress the development of viral and tumor immune responses. Moreover, iNKT cell adoptive transfer into flu-infected mice has been shown to abolish the expansion and flu-induced suppressive activity of the MDSCs in a CD1d- and CD40-dependent manner. However, the mechanisms by which this relatively small subset of T cells influence myelopoiesis and MDSC differentiation remain largely unknown. In this manuscript we firstly better define the MDSCs found in flu-infection as IL-10-secreting neutrophils that can suppress T cell proliferation. We then go further to show that the flu-induced ability to suppress T cells is acquired as early as the level of the Granulocyte-Macrophage Progenitors (GMPs) in the bone marrow and that iNKT cells can not only abrogate the suppressive activity of the IL-10-secreting neutrophils in the periphery but also that of the GMPs by a direct CD1d-dependent GCSF-mediated crosstalk. MDSC expansion has previously been shown to be associated with the expression of the myeloid-related protein S100A9, and the mechanism of action of granulocytic-MDSCs shown to be ARG1-dependent. We built upon both these findings to show that iNKT cells influence the expansion and function of the MDSCs in part by regulating S100A9 and ARG1 expression. Following this we then showed for the first time that the acute phase protein Serum Amyloid A (SAA), shown to increase during flu-infection, has a dual reciprocal role: having the ability to up-regulate S100A9 and ARG1 in myeloid cells and differentiate IL-10-secreting suppressive neutrophils, while simultaneously facilitating the ability of the MDSCs to crosstalk with iNKT cells in a CD1d-dependent GCSF-mediated manner to abrogate the SAA-induced suppressive activity. All together the data highlights the complexity of the immune response and the role iNKT cells play in influencing the differentiation of MDSCs during demand-driven myelopoiesis. More importantly however, it further affirms that research into harnessing the immunomodulatory capacity of iNKT cells remains an exciting prospect in bolstering future vaccination strategies and should continue to be pursued.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:629479 |
| Date | January 2011 |
| Creators | Arscott, Ramon |
| Contributors | Cerundolo, Vincenzo |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:07ab563a-7455-4f69-bca0-3b409b72d2f7 |
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