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Resumen de Role of hematopoietic stem and progenitor cells in training immunity against infection

Cristina Bono Tapp

  • During an infection, haematopoiesis is altered to increase the output of mature myeloid cells to fight off the pathogen. It has been demonstrated that the detection of pattern recognition receptor agonists by hematopoietic stem and progenitor cells (HSPCs) induces their differentiation towards mature myeloid cells with modified phenotypes.

    In the present PhD thesis, we show that an in vitro transient exposure of HSPCs to live Candida albicans cells is sufficient to induce a trained phenotype of the macrophages they produce in a dectin-1- and TLR2-dependent manner. Additionally, we use an HSPC transplantation mouse model to demonstrate that the direct interaction of β-glucans and their receptor (dectin-1) on HSPCs in vivo induces myeloid differentiation. Functionally, macrophages derived from HSPCs exposed to β-glucan in vivo produce higher levels of inflammatory cytokines, demonstrating that trained immune responses, already described for monocytes and macrophages, also take place in HSPCs. Using a similar in vivo model of HSPC transplantation, we demonstrate that inactivated yeasts of C. albicans induce differentiation of HSPCs through a dectin-1- and MyD88-dependent pathway. Regarding the mechanisms initiating myeloid development, we found that soluble factors produced following exposure of HSPCs to dectin-1 agonists act in a paracrine manner to induce differentiation towards trained macrophages, while TLR2 stimulation of HSPCs promotes myelopoiesis directly by initiating an MyD88-dependent signalling that involves a combined activation of the transcription factors PU.1, C/EBPβ and IRF7 driven by TBK1 and PI3K/mTOR.

    Moreover, we used a C. albicans live vaccine mouse model to reveal the mechanisms that drive trained immunity in vivo. We show that vaccination protects mice against a secondary infection and increases the number of bone marrow and, especially, splenic trained monocytes. Moreover, vaccination expands and reprograms HSPCs early during infection and mobilizes them transiently to the spleen to produce trained macrophages. Besides being primed for myeloid cell production, trained HSPCs are also reprogrammed to produce a greater amount of proinflammatory cytokines in response to a second challenge and their adoptive transfer is sufficient to protect mice against reinfection. Mechanistically, autocrine GM-CSF activation of HSPCs is responsible for the trained phenotype and essential for the vaccine-induced protection.

    Taken together, these findings reveal a fundamental role for HSPCs in sensing pathogens during infection and contributing to host protection, opening new avenues for disease prevention and treatment.


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