Sporri, Roman Andreas; (2003) Reciprocal control of T cell- and APC-activation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Antigen-specific interactions between antigen-presenting cells (APC) and T cells result in the reciprocal activation of T cells and APC and are necessary for both cell types to become fully functional effectors. Here, I studied two aspects of this process, namely (i) the specificity of TCR/MHC interactions and (ii) feedback signals from T cells to dendritic cells (DC), the most prominent APC type. Firstly, I investigated the influence of self-peptide/MHC complexes on the response of T cells to a foreign peptide. The vast majority of MHC molecules present peptides derived from self proteins. I wondered if this "sea'' of MHC molecules loaded with self peptides can affect the response of CD8+ T cells to foreign peptide. To this end, I used a monoclonal antibody to measure pOVA/H-2Kb complexes on TAP-/- versus TAP+/+ APC and correlated this with the ability of either APC type to activate pOVA-specific T cells. Surprisingly, T-cell activation was not affected by expression of TAP by APC and depended exclusively on the absolute amount of presented pOVA. These results imply that the repertoire of self-peptide/MHC complexes presented by APC has a negligible effect on the response of CD8+ T cells to foreign ligand. Secondly, I studied the role and functional implications of feedback signals from activated T cells to DC using both in vitro and in vivo approaches. I found that during T-cell priming, newly-activated T cells deliver signals that can promote the activation of both DC that do and DC that do not present the relevant peptide (cis or trans, respectively). However, T cell-derived signals are not sufficient to induce full DC activation in that they do not result in the secretion of cytokines important for T-helper cell differentiation such as IL-12p70, unless the DC has received a prior signal in the form of a microbial product. In the latter case, T cell signals can augment IL-12p70 production but this is strictly dependent on interactions in cis and does not function in trans. My results suggest that T cell signals that modulate the surface phenotype of DC vary from those necessary for DC functions controlling T helper cell polarisation.

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