Biochemical and Biophysical Research Communications
TRAF5 promotes plasmacytoid dendritic cell development from bone marrow progenitors
Introduction
Dendritic cells (DCs) comprise two distinct subsets: conventional and plasmacytoid DCs, cDCs and pDCs, respectively. pDCs were originally identified as a cell population that produces type 1 interferon in response to viral infection [1], and subsequently found to exert this cytokine response through ligation of Toll-like receptors (TLRs) 7 and 9 via Interferon regulatory factor 7 (IRF7) [1,2]. pDCs play an important role in host defense against various types of pathogen infection [3,4].
Both pDCs and cDCs derive from common DC progenitors (CDPs) in bone marrow (BM), and their development is crucially regulated by several transcription factors (TFs). Among them, Basic helix-loop-helix TF E2-2 (also known as Transcription factor 4 (TCF4)) is critical for cell commitment of CDPs toward pDCs, whereas DNA-binding protein inhibitor ID2 is essential for cDC differentiation [[5], [6], [7]]. Indeed, deletion of TCF4 leads to downregulation of TFs SPIB and BCL11A, which are necessary for the optimal pDC development, thereby reducing the number of pDCs generated [[5], [6], [7], [8]]. Meanwhile, the TCF4-deficiency in pDC precursor cells enhances the expression of ID2 and tips the balance toward cDCs [6]. Such balance between TCF4 and ID2 expression has been proposed to determine the selective pDC versus cDC development from BM progenitors [9].
Tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) is an adaptor protein that transduces intracellular signals from various TNF receptors, such as CD27 and CD40 [10]. In addition, recent studies demonstrate that TRAF5 negatively regulates IL-6 receptor signaling in CD4+ T cells [11,12] and TLR signaling in B cells [13]. TRAF5 therefore limits signaling processes of receptors in both positive and negative ways. On the other hand, the roles of TRAF5 in non-lymphoid cells have been less well studied. In this regard, we recently reported that TRAF5 restrained the function of mature pDCs and thereby regulated the wound healing process in the skin [14]. However, it remains to be clarified whether TRAF5 controls the development of pDCs in BM and the homeostasis of pDCs in peripheral lymphoid tissues.
In this study, we demonstrate a novel function of TRAF5 as a positive regulator of pDC development from BM progenitors.
Section snippets
Mice
C57BL/6 CD45.2+ wild-type (WT) mice were purchased from Japan SLC. Traf5−/− and CD45.1+ WT mice are previously described [11,15,16]. OT-I T cell receptor (TCR)-transgenic mice were provided from W. Heath (Walter and Eliza Hall Institute, Melbourne, Australia) and used as a source of CD8+ T cells specific for an ovalbumin (OVA)257–264 peptide [17]. All mice were bred and maintained under specific pathogen–free conditions at the Institute for Animal Experimentation, Tohoku University Graduate
TRAF5 promotes pDC development from BM progenitors in a cell-intrinsic manner
To determine whether TRAF5 is required for pDC differentiation, we first analyzed the proportion of pDCs and cDCs in WT versus Traf5−/− mice. pDCs in BM and spleen were fewer in Traf5−/− mice while type 1 and 2 cDCs (cDC1 and cDC2, respectively) were equally present between the two groups (Fig. 1A and B; gating strategy is shown in Supplementary Fig. 1). The fraction of CDPs in BM was similar between the two animals examined (Fig. 1C). These results suggest that TRAF5 positively regulates pDC
Discussion
In the present study, we addressed the role of TRAF5 in pDC differentiation. We found that TRAF5 promotes the expression of TFs that are necessary for pDC development in BM, thereby contributing to the optimal homeostasis of the same DC subset in the periphery in a cell-intrinsic fashion. On the other hand, TRAF5 has no clear effect on cDC subpopulations in steady-state conditions. Together these observations reveal a previously unknown function of TRAF5 in pDC development.
TRAF5 can support
Declaration of competing interest
The authors declare no conflicts of interest.
Acknowledgments
We thank H. Nakano for providing us with Traf5-deficient mice. We are also grateful to the Biomedical Research Core and the Institute for Animal Experimentation (Tohoku University Graduate School of Medicine) for their technical assistance. This work was supported by JSPS KAKENHI Grant Numbers 16K15508 (NI), and JP15H04640 (TS), and JP18H02572 (TS).
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