Calcineurin/NFAT signalling inhibits myeloid haematopoiesis

Abstract

Nuclear factor of activated T cells (NFAT) comprises a family of transcription factors that regulate T cell development, activation and differentiation. NFAT signalling can also mediate granulocyte and dendritic cell (DC) activation, but it is unknown whether NFAT influences their development from progenitors. Here, we report a novel role for calcineurin/NFAT signalling as a negative regulator of myeloid haematopoiesis. Reconstituting lethally irradiated mice with haematopoietic stem cells expressing an NFAT-inhibitory peptide resulted in enhanced development of the myeloid compartment. Culturing bone marrow cells in media supplemented with Flt3-L in the presence of the calcineurin/NFAT inhibitor Cyclosporin A increased numbers of differentiated DC. 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. The finding that inhibition of NFAT enhances myeloid development provides a novel insight into understanding how the treatment with drugs targeting calcineurin/NFAT signalling influence the homeostasis of the innate immune system.

The Calcineurin-NFAT Axis Controls Allograft Immunity in Myeloid-Derived Suppressor Cells through Reprogramming T Cell Differentiation

“…However, the mechanisms by which CsA could alter the innate immune system and thereby decrease allograft immune inflammatory injuries remain largely unknown. Calcineurin signaling was shown to negatively regulate myeloid lineage development (45,46). The susceptibility to fungal infection caused by CsA was also shown to be the consequence of an innate immune pathway regulating antifungal resistance in neutrophils (47).…”

“…Although NFATs have been extensively studied in the context of T cells, relatively few studies have examined their function in myeloid lineages. However, several recent studies about calcineurin signaling in innate immune effects have showed their NFAT-dependent regulatory effects (45)(46)(47)(48). In the present study, we demonstrate the intrinsic regulatory effects of MDSCs in prolonging allograft survival and show a previously unknown feature of MDSC function in immunohomeostasis, i.e., the reprogramming of T cell differentiation from T H 1 to T H 2 and CD8 ϩ T cell differentiation, which represents a novel mechanism of calcineurin amelioration of transplant immunological rejection by targeting the NFAT signaling pathway.…”

NFAT control of innate immunity

“…12 The NFAT pathway has since been studied extensively in lymphocytes, but a key role for this signaling pathway in myeloid cells has now also been identified. 3,8,9 The classic calcineurin/NFAT signaling pathway in lymphocytes has been reviewed in detail elsewhere. 11,13 In brief: on antigen engagement of lymphocyte receptors, phospholipase C-␥ (PLC-␥) becomes activated and hydrolyzes phosphatidylinositol-4,5-bisphosphate into inositol-1,4,5-trisphosphate (IP 3 ) and diacylglycerol.…”

“…8 In addition, NFAT signaling has been shown to negatively regulate myeloid cell development. 9 Accordingly, NFAT expression levels are down regulated during myeloid differentiation of hematopoietic CD34 ϩ stem cells (HSCs). 10 These data indicate that, in addition to betterknown roles for NFAT in lymphoid development, 11 the calcineurin/NFAT pathway plays a critical role in the development and function of innate myeloid cells.…”

NFATc1 releases BCL6‐dependent repression of CCR2 agonist expression in peritoneal macrophages fromSaccharomyces cerevisiaeinfected mice

“…46: 634-646 Burkitt lymphoma cells suggesting that this interaction is involved in normal and malignant B-cell development ([36, 37], and our unpublished data). The role of CN/NFAT signaling pathway in innate immunity was mainly investigated using CN inhibitors and/or by overexpression of a constitutively active version of CN-B (PPP3CB) [6,38,39]. Certainly informative, this approach neglected the individual properties of four related but different CN-dependent NFATc factors that, in addition, are expressed as multiple protein isoforms in a cell-type specific manner.…”