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tel-00827710, version 1 - 29 May 2013 (a) T cell diversity (i) T cell affinity Upon encountering an antigen-presenting DC, T cells that are specific for the epitope presented on MHC-I will proliferate. The strengh of the signal, the environmental conditions and the number of different epitopes presented by DCs will all influence the number of T cell clones that will proliferate. (ii) Memory potential Multiple subsets of effector CD8 + T cells have been identified based on their ability to become memory cells. After antigen clearance, the effector T cell population undergoes a dramatic decrease in numbers, known as the “contraction phase”, mediated mostly by apoptotic cell death. 5-10% of antigen-specific T cells survive this transition and make up the memory T cell pool. This latter subset is characterized by stem-cell-like properties such as slowed cell cycling, longer survival, telomerase expression and the ability of self-renewal. The initial events during T cell activation and signals from the microenvironment during stimulation impact the differentiation of effector T cells toward a terminally differentiated cytotoxic phenotype or toward a memory phenotype. First, the Short-Lived Effectors Cells (SLECs) are characterized by high expression of KLRG1 and low expression of IL-7Rα. These cells exhibit stronger effector function potential. In contrast, the Memory Precursor Effector Cells (MPECs) are KLRG1 low and IL-7Rα high and are more likely to become memory cells (Joshi et al., 2007). Thes distinctions are not absolute, as both subset populations are highly heterogenous. A more accurate depiction of effector CD8 + T cell population heterogeneity would be represented by a continuum with the MPEC phenotype at one extreme, the SLEC at the other extreme, and intermediately differentiated effector cells between these two set phenotypes (Figure 9) (Cui and Kaech, 2010). Several transcription factors have been described that control T cell differentiation. An expression gradient of T-bet has been identified as a critical cell fate decision factor between terminal effector versus memory differentiation and is highly expressed in SLECs (Joshi et al., 2007). In contrast, Eomesodermin (Eomes) acts either in synergy or in opposition with T-bet to favor memory differentiation (Intlekofer et al., 2007; Intlekofer et al., 2005). Other factors such as Blimp-1, Bcl-6 or Id2 have also a role in this mechanism (Cui and Kaech, 2010). Inflammatory signals such as IL-12 can regulate these transcription factors and thus influence the outcome of T cell differentiation in the context of an inflammatory response (Takemoto et al., 2006). 48

tel-00827710, version 1 - 29 May 2013 Figure 9. Effector and memory T cell differentiation upon activation. SLO, secondary lymphoid organ, SLEC, Short-lived effector cell, MPEC, Memory precursor effector cell, TEM, effector memory T cell, TCM, central memory T cell. Figure from Cui et al. 2010. (iii) T cell quality The quality of the T cell response was first characterized by measuring its magnitude, represented by the frequency of antigen-specific T cells and their ability to secrete IFNγ following antigen-specific restimulation using techniques such as IFNγ-ELISPOT. However, the use of only a few parameters to define the quality of the response and its ability to confer a protection is often not sufficient (Seder et al., 2008). For instance, the magnitude of the HIV-specific CD8 + T cell response alone does not predict the progression of the disease (Gea- Banacloche et al., 2000). However, by comparing the T cell responses in patients that are long-term non-progressors to those of progressors, it has been shown that T cell function is not equivalent between these two groups, and that these differences could explain the range of disease progression and outcome phenotypes in these two patient groups. In general, all the effector T cells are not functionally identical. While some T cells secrete only one cytokine such as IFNγ, others are able to secrete several cytokines once activated. These polyfunctional T cells have been demonstrated to be critical for mounting an efficient response in multiple disease models. Practically speaking, T cells can be characterized both by their surface markers expression and also by their various functions, including the ability to secrete cytokines, cytolytic activity or proliferative capacity. The development of more advanced techniques such as Page 49 of 256

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