Voie d'immunisation et séquence d'administration de l ... - TEL

tel-00827710, version 1 - 29 May 2013
why further, detailed understanding of the factors regulating T cell responses as well as the
precise action mechanisms of vaccines and other agents is essential. In parallel, efficient
experimental strategies to accurately evaluate the antigen-specific CD8 + T cell response must
be developed in order to compare different methods of treatment administration, and to
determine the efficiency of novel approaches.
In this introduction, I will first present the mechanism of dendritic cell-mediated antigen
presentation and the development of antigen-specific T cell responses. Next, I will review
how this process can be modulated by the use of different forms of antigen or adjuvants to
boost the resulting T cell response. To conclude, I will describe the existing techniques to
study these questions in experimental mouse models, detailing their advantages and
limitations in a context where it is important to remain as close as possible to physiologic
conditions, such that the results can be applied to questions of human immunity.
I. ANTIGEN PRESENTATION BY DENDRITIC CELLS
A. Mechanisms of antigen presentation
Upon the initiation of an immune response, antigen is identified and taken up by antigen-
presenting cells (APCs) that proceed to process and present it to specific T cells, resulting in
antigen-specific T cell-mediated immunity. The classical view of antigen presentation is
divided into two mechanisms: (i) antigens acquired from the extracellular environment
(exogenous antigens) are processed and presented on MHC-II molecules and induce the
activation of CD4 + T cells; (ii) antigens originating from the endogenous proteins (either self
protein or viral proteins expressed upon infection) are presented on MHC-I molecules,
leading to the activation of CD8 + cytotoxic T cells. However, a third mechanism has also
been described: the cross-presentation pathway, in which extracellular antigens are presented
on MHC-I molecules, allowing for the development of a specific CD8 + T cell response. This
pathway is now known to be critical for the development of a cytotoxic T cell response
against viruses that do not directly infect APCs or against tumors derived from non-APCs. In
vitro many cells are able to cross-present antigen (DCs, macrophages, B cells); however DCs
are the main antigen cross-presenting cell in vivo (Heath et al., 2004; Kurts et al., 2001). A
detailed overview of these mechanisms will be discussed below.
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