Differential effects of inhibition of bone morphogenic protein (BMP) signalling on T‐cell activation and differentiation

Abstract

Bone morphogenetic proteins (BMPs) are involved in patterning and cellular fate in various organs including the thymus. However, the redundancy of BMPs and their receptors have made it difficult to analyse their physiological roles. Here, we investigated the role of BMP signalling in peripheral CD4 1 T cells by analysing the effects of an inhibitor of BMP signalling, dorsomorphin. Dorsomorphin suppressed phosphorylation of SMAD1/5/8, suggesting that BMP signalling naturally occurs in T cells. At high doses, dorsomorphin suppressed proliferation of T cells in a dose-dependent manner, inducing G1 arrest. Also, dorsomorphin suppressed Th17 and induced Treg-cell differentiation, while preserving Th2 differentiation. Dorsomorphin efficiently suppressed IL-2 production even at low doses in mouse CD4 1 T cells, suggesting that the BMP-Smad signalling physiologically regulates IL-2 transcription in these cells. In addition, recombinant BMP2 induced a dosedependent multiphasic pattern of IL-2 production, while Noggin suppressed IL-2 production at higher doses in Jurkat cells. Notably, BMP signalling controlled the phosphorylation of RUNX1, revealing the molecular nature of its effect. Collectively, we describe multiple effects of dorsomorphin and Noggin on T-cell activation and differentiation, demonstrating a physiological role for BMP signalling in these processes.

A Critical Role for Transcription Factor Smad4 in T Cell Function that Is Independent of Transforming Growth Factor β Receptor Signaling

“…Therefore, Smad4 may control T cell proliferation through many diverse pathways independent of TGF-β. BMP signaling may be involved in this process as it has been suggested that BMP signaling is important for T cell proliferation (Yoshioka et al, 2012). We found that Smad4 is required for optimal Myc expression in T cells.…”

Modulation of bone morphogenic protein signaling in T-cells for cancer immunotherapy

“…In many cell types, signaling pathways initiated by ligand binding to BMPR1α intersect with multiple other pathways including those important for T R cell generation and function (like Wnt, Akt/mTOR, Notch); however, the extent of these interactions in T-cells is not well known (Tian et al, 2005; Itasaki and Hoppler, 2010; Poorgholi et al, 2012). In mature T-cells, inhibition of signaling through BMP was found to produce complex effects that included inhibition of T H 17 cell differentiation and IL-2 production (Yoshioka et al, 2012). BMP and activins augment T R cells generation, acting syner-gistically with TGFβ (Huber et al, 2009; Itasaki and Hoppler, 2010; Lu et al, 2010).…”

Carotenoid Cleavage Oxygenases from Microbes and Photosynthetic Organisms: Features and Functions

“…By contrast, the largest number of CCD4 genes has been found in Citrus sp. (a, b1, b2, c and d), Populus trichocarpa (a–e), and Chrysanthemum morifolium (a-1–a-4 and b), with five members and with at least one of them being a putative pseudogene [115,133,145,146]. Four members have been identified in Vitis vinifera (grapevine) (a, b, c, and e) or Brassica napus (rapeseed) (A1, A8, C1, and C3), while three are present in Theobroma cacao (cacao) [98,130].…”

“…In particular, the exclusive cleavage activity reported for citrus CCD4b1 and CCD4, together with its restricted expression pattern, may indicate that this enzyme belongs to a novel class of CCD more functionally related to the recently characterized CCD2 from saffron [117,118]. In planta data, derived from the analysis of apocarotenoid profiles, the alteration in carotenoid complement in ccd4 mutants and overexpressed or repressed CCD4 plants, or both, point to xanthophylls as the preferential substrates in vivo [130,133,134,145]. Nevertheless, in some species and tissues, such as potato tubers, chrysanthemum petals, and peach fruit, β-carotene cannot be ruled out as the primary target since alterations in the xanthophylls composition in defective or overexpressing CCD4 plants can be explained by a reduction or increase in β-carotene content as the precursor of β-xanthophylls [136,150,153].…”