The development of protective immune responses against respiratory viral infections requires the coordinated actions of components of innate and adaptive immunity. Key to the induction of adaptive immune responses is the acquisition of viral antigen in peripheral tissues by antigen presenting cells, such as dendritic cells (Des) and the transport of the antigen to regional lymphoid tissue for presentation to T lymphocytes. Accumulating evidence suggests that chemokines play an important role in the development of protective Immune responses. Although primarily recognised for their ability to regulate the migration of cells of the immune system, it has become clear that chemokines exert a variety of effects on immune cells. We, and others, have demonstrated that the chemokine eeL3 is required for the development of protective antiviral immunity against respiratory viruses. Surprisingly this effect is not due to a requirement for CCL3 in regulating the migration of effector T cells to the infected tissue. In the current study I have examined the effect of eeL3 on the maturation and function of Des using two De cell lines. Des are the most potent antigen presenting cells in the body. In their immature state they infiltrate infected tissues and pick up foreign antigens for presentation to T cells. The interaction between the De and the antigen, in concert with cytokines released at the site of infection, triggers a pathway of differentiation in the Des resulting in their phenotypic and functional conversion into mature Des. These mature Des are poor at taking up antigen but, by virtue of their enhanced surface expression of eo stimulatory molecules together with their ability to secrete immunomodulatory cytokines, they are highly effective at stimulating T cell responses. The data obtained in this study indicate that eeL3 does not promote complete or partial maturation of DCs indicating that the mechanism whereby CCL3 promotes the development of protective immunity is independent of DC maturation. In contrast, these data indicate that CCL3 enhances the ability of DCs to take up soluble antigen. The uptake of FITC-conjugated HSA was increased eight-fold by treatment of the lA WSII dendritic cell line with CCL3 and this increased uptake was inhibited by mannan, an inhibitor of the mannose receptor-dependent pathway of uptake. The ability of DCs to acquire particulate antigen was not augmented by CCL3, suggesting the differential regulation of these two pathways of antigen uptake. CCL3 treatment also enhanced the ability of influenza A-infected lA WSII cells to present the MHC class I-restricted influenza NP366 epitope to an NP366-specific T cell hybridoma. CCL3-dependent enhancement of antigen presentation was not restricted to the lA WSII cell line. Using an independent approach, it was found that presentation of an epitope contained in influenza A haemagglutinin, HA258 (defined in this research), is also augmented by CCL3 treatment of another dendritic cell line, tsDC. We propose that the enhancement of DC-mediated antigen uptake and presentation by CCL3 contributes to the CCL3-dependent development of protective antiviral immunity in vivo.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:551505 |
| Date | January 2011 |
| Creators | Yaragandla, Ravi |
| Publisher | University of Ulster |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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