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Environmental sensing by immune cells
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Resumo(s)
Environmental signals that can be obtained from nutrients, or from different cell network, such as the nervous system can influence the immune system. Every year more molecular and cellular links are discovered, connecting non-immune cells and non-typical immune signals to immunological responses. Haematopoiesis is a tightly regulated process responsible for the generation of all blood cells sustained by a minute cell population of haematopoietic stem cells (HSC). Many molecular and cellular components are involved during this road of lineage commitment, namely proteins from the tyrosine kinase family. Within this family the tyrosine kinase receptor RET, a proto-oncogene normally associated with kidney and enteric nervous system function, has also been described in haematopoietic cells and lymphoid organs. However, the role of RET in haematopoiesis is completely unexplored, and the mechanisms that regulate HSC homeostasis and function remain largely unknown. We found that HSCs express RET and that its neurotrophic factor partners are produced in the HSC environment. Ret ablation induced impaired survival and reduced numbers of HSC with normal differentiation potential, but loss of cell-autonomous stress response and reconstitution potential. Remarkably, downstream of p38/MAP kinase and CREB activation, RET signals provided HSCs with critical Bcl2 and Bcl2l1 surviving cues. Therefore, enforced expression of RET down-stream targets, Bcl2 or Bcl2l1, was sufficient to restore the activity of Ret null progenitors in vivo. Improved HSC survival, expansion and in vivo transplantation efficiency was also achieved when activation of RET was stimulated. Finally, we saw that human cord-blood progenitor expansion and transplantation was also improved by neurotrophic factors. This opens new horizons to explore the use of RET agonists in human HSC transplantation. Our work shows that RET tyrosine kinase drives HSC survival, expansion and function, making neurotrophic factors novel components of the HSC microenvironment. HSCs and neurons are therefore regulated by similar signals. In the last years, a lot of attention has been given to dietary compounds and nutrition in the immune system. Vitamin A, or its metabolite Retinoic acid (RA), signalling has been shown to modulate different arms of the haematopoietic tree namely by imprinting gut homing markers, by influencing T cell polarization and function, modulate innate immune responses, etc. Invariant Natural Killer T cells (iNKTs) are cells that share properties with both T and Natural Killer cells and that respond to lipid antigen presented by the non-classical MHC class-I like, the CD1d molecule. Unusually, these cells express an extremely limited and conserved T cell repertoire and upon stimulation they respond rapidly, producing substantial amounts of cytokines, placing them between the innate and acquired immune system. In terms of function, NKTs play important roles in immune regulation, tumour surveillance and host defence against pathogens. We found that RA modulates NKT cell development. Ablation of retinoic acid signalling using mice bearing a dominant negative form of the Retinoic Acid Receptor alpha (RARa) in cells expressing the CD4, lead to a cell-autonomous decrease of total iNKTs in the thymus, spleen and liver. Interestingly, when dissecting the stages of development, we observed no significant differences in the numbers of iNKTs at the stage 0 while stages 1-3 were profoundly affected. Stage 1 NKT cells from CD4CreRARaDN animals had a noticeable reduction in their proliferative capacity which correlated to the developmental block from this stage onwards. Finally, adoptive transfer of littermate control liver NKT cells into CD4CreRARaDN and in vivo activation of iNKT cells via their lipid ligand, alpha-galactocylceramide, provided partial but significant protection in the context of B16F0 melanoma model. Our preliminary findings support that RA signalling impacts the development of iNKT cells, which are key players in tumour immunology.
Taken together, our results clearly suggest RET as a novel molecule in haematopoiesis, favouring the concept that during evolution, molecular mechanisms previously thought to be used by specific tissues can become more widely used to mediate the function of different systems and that RA is key for the development of iNKTs, thus establishing a molecular link between nutritional cues, the immune system and the control of tumour progression and outcome.
Descrição
Tese de doutoramento, Ciências Biomédicas (Imunologia), Universidade de Lisboa, Faculdade de Medicina, 2018
Palavras-chave
Meio ambiente Interacção gene-ambiente Hematopoiese Vitamina A Células T matadoras naturais Teses de doutoramento - 2018