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

tel-00827710, version 1 - 29 May 2013
are required for the uptake of soluble antigens. Once the antigen is inside the cell, it can be
processed and the resulting peptides are presented on MHC-I or MHC-II molecules.
(a) Antigen uptake
(i) Diversity of engulfment receptors
Extracellular antigens must be detected and engulfed by cells prior to their processing and
presentation. A diverse repertoire of receptors exists to modulate the engulfment process and
the pattern of expression of these receptors varies from one APC subset to another. As
examples, scavenger receptors, mannose receptor, DEC-205, Langherin, Fc receptors, and
Dectin-1 can all mediate antigen uptake. The engulfment receptor choice is critical, as
depending on the receptor engaged, the outcome of the immune response may vary (Burgdorf
and Kurts, 2008).
(ii) The particular case of dying cells
Upon the death of a cell from any cause, the cellular remnants must be removed quickly to
preserve tissue homeostasis. Depending on the mechanism of cell death involved, this
clearance is accompanied by tolerance and tissue repair or activation of an immune response.
The dying cells advertise their presence through the release of “find-me” signals such as
sphingosine-1-phosphate or the nucleotides ATP or UTP (Ravichandran, 2011). These
molecules promote the recruitment of phagocytes and enhance their activity. Phagocytes
identify the dying cells via the expression of “eat-me” signals. For example,
phosphatidylserine is a lipid that is present in the inner leaflet of the plasma membrane in live
cells. When a cell undergoes apoptosis, this lipid is exposed on the outer membrane and can
then act as an “eat-me” signal for phagocytes surveying the local environment. In addition,
changes in charge and/or glycosylation can be detected on the surface of dying cells. “Eat-
me” signals are most often recognized by scavenger receptors or complement receptors… In
the case of phosphatidylserine expression, the TIM molecule family can act as receptors for
phagocytosis (Miyanishi et al., 2007). Specifically, TIM4 is exclusively expressed on APCs
and mediates the phagocytosis of apoptotic cells. However, there exists a variety of TIM
receptors that allow for the detection of dying cells and result in functionally different
outcomes, particularly immune activation or tolerance, depending on the cell type and TIM
molecule engaged (Freeman et al., 2010). Another recently characterized receptor for dying
cells is Clec9A, which has been demonstrated to interact with necrotic cell (Sancho et al.,
2009). This receptor recognizes actin which is normally contained intracellularly and that is
exposed in dying cells upon necrosis (Ahrens et al., 2012; Zhang et al., 2012).
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