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

tel-00827710, version 1 - 29 May 2013
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Research Plan
The CD8 + T cell response is a critical component of the adaptive immune system. These cells
are considered particularly important for the host response to microorganisms and cells
undergoing malignant transformation. In order to carry out their effector function efficiently,
these cells must be activated by DCs, presenting MHC-I-peptide complexes. For many
infections and most tumors, an indirect presentation pathway (referred to as cross-priming) is
utilized for the loading of antigen onto the MHC-I of DCs. Although an effective CD8 + T cell
response is critical for the control of many diseases, including tumor growth, chronic viral
infection and other intracellular pathogens, vaccines capable of eliciting protective CD8 + T
cells have not yet been developed. In order to accomplish this goal, much work has been
performed to further understand the mechanisms of cross-priming and targeting this pathway
for the purpose of novel vaccination strategies. For instance, Fontana and colleagues have
conducted clinical studies utilizing a cell-associated antigen - peripheral blood lymphocytes
genetically modified to express tumor antigens - as a strategy for inducing tumor immunity in
cancer patients (Fontana et al., 2009).
Our laboratory has been interested in defining optimal strategies to cross-prime CD8 + T cells
after the delivery of cell-associated antigen. However, in the development of experimental
models, it has been important to prioritize establishing conditions that reflect the physiologic
situation present during the vaccination of humans, particularly in terms of antigen-specific T
cell frequency. In order to do this, we expanded upon a recently described tetramer-based
enrichment assay that allows for the detection of low numbers of antigen-specific T cells.
This strategy allowed us to work within relatively physiologic conditions, specifically in
terms of T cell precursor frequency, in order to investigate the impact of two important
parameters that must be taken into consideration by investigators interested in initiating
adaptive immune responses during vaccination - the route of vaccination and the use of
adjuvants.
I. IMPACT OF THE ROUTE OF IMMUNIZATION ON CD8 + T
CELL CROSS-PRIMING
To mimic the administration of cell-associated antigen and study the efficacy of the resulting
CD8 + T cell cross-priming, we used a well-characterized model of cross-presentation. Donor