Student Theses and Dissertations

Date of Award

2011

Document Type

Thesis

RU Laboratory

Nussenzweig Laboratory

Keywords

dendritic cells, activated monocytes, antigen targeting

Abstract

"Dendritic cells (DCs), which maintain tolerance and orchestrate T cell immune responses, comprise a heterogeneous group of cells. For example, in the steady state, murine spleen contains pre-DC-derived CD8+DEC-205+ and CD8-DCIR2+ conventional DCs. To examine antigen processing and presentation in vivo, antigens were specifically targeted to CD8+ and CD8- DCs using chimeric monoclonal antibodies. We find that CD8- DCs are better than CD8- DCs for presentation of exogenous antigens onto major histocompatibility complex (MHC) class II molecules due to cell intrinsic differences. DCs are responsible for initiating T cell responses. However, during inflammation, monocytes become activated and acquire some DC-like features such as expression of CD11c, MHCII and co-stimulatory molecules, yet their role in T cell activation is still a matter of investigation. Cells similar to DCs can also be produced in vitro by culturing monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) or bone marrow progenitors (pre-DCs) with fms-related tyrosine kinase ligand (FL). Although each of these cell types can present antigen, the relative efficiency of processing and presentation after antigen capture by different routes has not yet been systematically compared. To this end we administered OVA to various conventional DCs and activated monocytes by receptor-mediated endocytosis, pinocytosis or phagocytosis and measured antigen uptake and presentation to MHCI and MHCII restricted T cells. We find that CD8- DCs are more efficient than any other types of antigen presenting cells tested in terms of presenting antigen to MHCII restricted CD4+ T cells, irrespective of the route of antigen capture or maturation status. In contrast, both subsets of splenic DCs are equally efficient at cross-presenting antigens to CD8+ T cells. All DCs and activated monocytes cross-presented antigens delivered by receptor-mediated endocytosis and pinocytosis, albeit with different efficiencies. However monocyte-derived cells differ from DCs in that they are several orders of magnitude less efficient in presenting antigens captured by phagocytosis. DCs derived from pre-DCs are unique, processing and presenting antigens efficiently irrespective of the route of antigen capture. Our observations have significant implications for understating initiation of immune responses and vaccination strategies targeting DCs and activated monocytes."

Comments

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

Permanent URL

http://hdl.handle.net/10209/396

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