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

tel-00827710, version 1 - 29 May 2013
II. Mechanisms responsible for the opposite effects of poly i:c on cross-priming------------ 118
A. Mice available to study the effects of type I IFN on cross-priming--------------------------- 118
B. Inhibition of cross-priming upon early type I IFN production--------------------------------- 119
1) Type I IFN inhibit cross-priming through direct action on cross-presentation --------------------- 119
2) Type I IFN act on cDCs but cell-intrinsic production is not required ------------------------------- 121
3) Early poly I:C affects DC numbers and phenotype----------------------------------------------------- 122
4) Early poly I:C treatment affects antigen uptake -------------------------------------------------------- 125
5) Does early poly I:C treatment act directly on antigen-specific T cells? ----------------------------- 126
C. Enhancement of cross-priming after late type I IFN production ------------------------------ 127
1) Enhancement of cross-priming upon late poly I:C delivery is type I IFN-dependent ------------- 127
2) Late type I IFN enhance cross-priming at the level of antigen uptake and/or presentation ------- 128
3) Does late type I IFN act directly on antigen-specific CD8 + T cells?--------------------------------- 129
III. How to choose the optimal timing for adjuvant delivery? ----------------------------------- 130
Chapter 4: General discussion--------------------------------------------------------------------- 135
I. Tetramer-based enrichment: A powerful tool---------------------------------------------------- 137
A. Advantages and limitations------------------------------------------------------------------------- 137
1) Sensitivity of the technique -------------------------------------------------------------------------------- 137
2) Applications for human immunology -------------------------------------------------------------------- 138
3) Limitations --------------------------------------------------------------------------------------------------- 139
B. Future directions ------------------------------------------------------------------------------------- 140
1) Other antigenic models------------------------------------------------------------------------------------- 140
2) Improve the physiologic relevance of our model ------------------------------------------------------- 140
3) Other recently developed techniques --------------------------------------------------------------------- 141
II. Impact of the route of immunization on CD8 + T cell cross-priming ------------------------ 143
A. The route of immunization impacts the efficiency of CD8 + T cell cross-priming but not the
diversity of antigen-specific T cells--------------------------------------------------------------------- 143
1) Kinetic of the response ------------------------------------------------------------------------------------- 143
2) Quality of the response ------------------------------------------------------------------------------------- 143
3) Diversity of antigen-specific T cells---------------------------------------------------------------------- 144
B. Why does local immunization result in more robust T cell cross-priming? ----------------- 144
1) Nature of injected splenocytes ---------------------------------------------------------------------------- 144
2) In which circumstances does splenocyte engulfment occur? ----------------------------------------- 146
3) A role for antigen persistence? ---------------------------------------------------------------------------- 149
4) A role for CD4 help? --------------------------------------------------------------------------------------- 151
5) Different T cell activation depending on the timing of activation? ---------------------------------- 152
C. Clinical applications --------------------------------------------------------------------------------- 152
III. Combination of antigen with adjuvant ---------------------------------------------------------- 154
A. The timing of adjuvant delivery should be coordinated with antigen processing and
presentation------------------------------------------------------------------------------------------------- 154
1) Effects of poly I:C and type I IFN in our model -------------------------------------------------------- 154
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