Calcineurin/NFAT signalling inhibits myeloid haematopoiesis.
Bottom Line: Reconstituting lethally irradiated mice with haematopoietic stem cells expressing an NFAT-inhibitory peptide resulted in enhanced development of the myeloid compartment.Global gene expression analysis of untreated DC and NFAT-inhibited DC revealed differential expression of transcripts that regulate cell cycle and apoptosis.In conclusion, these results provide evidence that calcineurin/NFAT signalling negatively regulates myeloid lineage development.
Affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.Show MeSH
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Mentions: To extend these observations, we performed competitive reconstitution of irradiated hosts using mixed HSC lines in a 1:1 ratio; VIVIT-eGFP expressing HSCs as competitors to control tdTomato HSC lines. The ratio of VIVIT-eGFP to control-tdTomato derived granulocytes (CD11b+Gr1+), monocytes (CD11b+Gr1−), cDC (CD11c+MHCII+) and pDC (CD11c+B220+) was analysed in BM, spleen, lymph nodes and peripheral blood 8 weeks after engraftment. We observed a selective advantage for calcineurin/NFAT impaired cells in the repopulation of pDC, cDC, granulocytic and monocytic compartments throughout the BM, spleen, lymph nodes and peripheral blood (shown as log ratio of engrafted NFAT-impaired competitors to controls, Fig 2A). Critically, the relative proportions of lymphoid T and B cells remained unchanged and simply reflected the ratio of injected HSC (Fig 2A), indicating comparable engraftment of both HSC lines and confirming that lymphopoiesis is not impaired by this level of calcineurin/NFAT inhibition. The unaffected ratio of lymphocytes indicates that self-renewal and maintenance of stem cell progenitors is not affected by impaired NFAT signalling.
Affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.