Creusot, Remi Jerome; (2002) Particle-mediated DNA immunisation: CD4+ T cell priming and cooperation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In order to better understand how CD4+ T cells interact in vivo, a mouse model was established, involving the combined adoptive transfer of two populations of T cell receptor (TCR)-transgenic T cells and particle-mediated DNA delivery (PMDD) for the control of antigen presentation by dendritic cells. Since PMDD is a relatively recent method of immunisation, its effect on CD4+ T cells needed to be documented in the context of adoptive transfer models. These preliminary studies allowed the quantification of the CD4+ T cell responses to PMDD in vivo, and in particular, the appearance of specialised activated CD4+ T cells, namely Thl and Th2, and demonstrated the crucial role of cytokines in the early phase of the immune response. Such models should prove useful for testing the concomitant inoculation of DNA antigen and immunomodulators, in the scope of rectifying the balance between these T cell subsets as a strategy for the treatment of many pathological conditions. These models were also used to examine the influence of the genetic background and the dose of DNA administered. A comparative study on migration and activation of na'ive versus polarised CD4+ T cells was also carried out. To examine the cooperation between CD4+ T cells of different specificity, two populations of TCR-transgenic T cells recognising different antigens were co-transferred into the same adoptive host. PMDD was used as a tool for in vivo co-expression of two antigens, either on the same dendritic cell (linked) or not (unlinked). It was found that polarised T cells may considerably influence the fate of naive T cells according to their cytokine profile. Cytokines confined to the dendritic cell cluster microenvironment appeared to play a more important role in the instruction of responding T cells. Moreover, linked presentation of two antigens to clones with a high and a low clonal frequency resulted in a strongly enhanced activation and effector function in the latter. These results demonstrated that cooperation between CD4+ T cells dominates over competition, is more efficient upon linkage with the same antigen-presenting cell and leads to better T cell instruction / deviation.

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