Spécialisation fonctionnelle des cellules myéloïdes mononucléaires humaines dans l’induction des réponses T folliculaire helper

Abstract : T follicular helper cells (Tfh) play a key role in the establishment of efficient humoral responses. Indeed, Tfh are involved in B lymphocyte selection allowing the development of high affinity memory B cells and antibodies. Tfh are promising targets for new therapeutic strategies, especially to increase the effectiveness of vaccination. Thus, it is crucial to better understand the stages leading to their development, especially in human. Initiation of Tfh polarisation occurs in secondary lymphoid organs and involves mononuclear myeloid cells (MMC). MMC from secondary lymphoid organs include resident macrophages and three subsets of resident Dendritic Cells (DC): cDC1 (CD141+), cDC2 (CD1c+) and pDC. We were particularly interested in human MMC subsets respective roles in the induction of Tfh polarisation. Thus, the work carried out during my thesis aimed first at analysing the ability of different populations of MMC to induce Tfh polarisation, in order to highlight potential functional specialisations. In a second step, we focused on the molecular mechanisms involved in Tfh polarisation by MMC. We have shown a functional specialisation of cDC2 and tonsillar macrophages for Tfh polarisation. However, differences have been observed between cDC2 and macrophages, since macrophages induce secretion by T cells of a large amount of CXCL13 compared to cDC2, which are more effective in inducing IL21 production. We have also been able to show that cDC2 and macrophages secreted cytokines previously shown to play a role in Tfh induction such as IL12p70, ActivinA and TGFβ. In order to confirm the role of these cytokines in Tfh polarisation induced by tonsil MMCs, we used blocking antibodies in our T helper polarisation experiments. Thereby, we confirmed the role of IL12p70, Activin A and TGFβ in the induction of human Tfh. Our results also suggest a role for Activin A and TGFβ in inducing secretion of CXCL13, whereas IL12p70 would be involved in the induction of IL21 secretion. Besides, our results suggest the existence of two Tfh subsets characterised by expression of either IL21 or CXCL13. The work performed during my thesis broadens the knowledge on the functional specialisation of human DC subsets and macrophages, and provides new insight into the differentiation of human Tfh.
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Mélanie Durand. Spécialisation fonctionnelle des cellules myéloïdes mononucléaires humaines dans l’induction des réponses T folliculaire helper. Immunologie. Université Sorbonne Paris Cité, 2017. Français. ⟨NNT : 2017USPCB087⟩. ⟨tel-02134781⟩

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