Cbfβ2 deficiency preserves Langerhans cell precursors by lack of selective TGFβ receptor signaling

Tenno, Mari; Shiroguchi, Katsuyuki; Muroi, Sawako; Kawakami, Eiryo; Koseki, Keita; Kryukov, Kirill; Imanishi, Tadashi; Ginhoux, Florent; Taniuchi, Ichiro

doi:10.1084/jem.20170729

“…Apoptotic and necrotic cells were excluded by co-staining with eFluor450-labeled recombinant Annexin V and 7-AAD, respectively. Libraries for digital RNA sequencing 20,45 were prepared from 100 cells, as described previously 46 . Three independent libraries each were generated from M cells and epithelial cells with different sample indexes.…”

Section: Methodsmentioning

confidence: 99%

Osteoprotegerin-dependent M cell self-regulation balances gut infection and immunity

Kimura

¹

,

Nakamura

²

,

Kobayashi

³

et al. 2020

Self Cite

View full text Add to dashboard Cite

Microfold cells (M cells) are responsible for antigen uptake to initiate immune responses in the gut-associated lymphoid tissue (GALT). Receptor activator of nuclear factor-κB ligand (RANKL) is essential for M cell differentiation. Follicle-associated epithelium (FAE) covers the GALT and is continuously exposed to RANKL from stromal cells underneath the FAE, yet only a subset of FAE cells undergoes differentiation into M cells. Here, we show that M cells express osteoprotegerin (OPG), a soluble inhibitor of RANKL, which suppresses the differentiation of adjacent FAE cells into M cells. Notably, OPG deficiency increases M cell number in the GALT and enhances commensal bacterium-specific immunoglobulin production, resulting in the amelioration of disease symptoms in mice with experimental colitis. By contrast, OPG-deficient mice are highly susceptible to Salmonella infection. Thus, OPGdependent self-regulation of M cell differentiation is essential for the balance between the infectious risk and the ability to perform immunosurveillance at the mucosal surface.

show abstract

“…We have demonstrated the dissociation of EpCAM and Langerin expression by LC precursors, markers previously thought to be expressed concomitantly only by mature cells (43). EpCAM + cells are highly transient, but expressed a unique gene profile that clearly identifies them as distinct from both blood monocytes and mLC.…”

Section: Discussionmentioning

confidence: 73%

“…Culture of BM cells with GM-CSF led to the expansion of Flt3 + and CD115 + cDC and moDC, and CD115 + macrophages, based on the gating strategy published by the Reis e Sousa group ( Figure S2) (41). By comparison, culture of BM cells with GM-CSF and TGFβ to generate BM-LC (20,43,44) demonstrate a more heterogeneous profile within EpCAM + DEC205 + cells with subsets of both CD115 + and CD115 neg cells. However, there was no contribution of CD135 + cells to the LC-like cells in these cultures, mirroring our in vivo findings ( Figure 2D).…”

Section: Lineage Cells Do Not Become Long-term Replacement Lcmentioning

confidence: 99%

“…CD11b + cells. Mature LC are identified by the unique concomitant expression of high levels of the cell adhesion molecule EpCAM (CD326) and the C-type lectin receptor, Langerin (CD207), which are simultaneously up-regulated upon differentiation of eLC (9,19,43). By contrast, 'shortterm' LC, do not up-regulate EpCAM (18).…”

Section: Lc Repopulation Is Preceded By a Single Wave Of Donormentioning

confidence: 99%

“…We next used an in vitro screen to identify the growth factors, in addition to TGFβ, that controlled Id2 expression and LC identity after differentiation from BM cells. We selected BMP7, CSF-1 and IL-34 based on expression of their cognate receptors (BMPR1a and CSF1R respectively) by EpCAM + cells in vivo ( Figure S8C) and their requirement for LC repopulation after UV-irradiation (43,52,53), and tested the impact of each factor on LC development in BM cultures. IL-34, but not CSF-1 or BMP7 specifically enhanced LC numbers ( Figure 6C), and this was associated with the specific up-regulation of Id2 by LC in IL-34 cultures ( Figure 6D).…”

Section: Mean Interdivision Time In Mlcmentioning

confidence: 99%

See 2 more Smart Citations

A single wave of monocytes is sufficient to replenish the long-term Langerhans cell network after immune injury

Ferrer

¹

,

West

²

,

Henderson

³

et al. 2019

Preprint

0

View full text Add to dashboard Cite

Embryo-derived Langerhans cells (eLC) are maintained within the sealed epidermis without contribution from circulating cells. When the network is perturbed by transient exposure to ultra-violet light, short-term LC are temporarily reconstituted from an initial wave of monocytes, but thought to be superseded by more permanent repopulation with undefined LC precursors. However, the extent to which this mechanism is relevant to immune-pathological processes that damage LC population integrity is not known. Using a model of allogeneic hematopoietic stem cell transplantation, where allo-reactive T cells directly target eLC, we have asked if and how the original LC network is ultimately restored. We find that donor monocytes, but not dendritic cells, are the precursors of the long-term LC in this context. Destruction of eLC leads to recruitment of a single wave of monocytes which engraft in the epidermis and undergo a sequential pathway of differentiation via transcriptionally distinct EpCAM+ precursors. Monocyte-derived LC acquire the capacity of self-renewal, and turn-over in the epidermis was remarkably similar to that of steady state eLC. However, we have identified a bottleneck in the differentiation and survival of epidermal monocytes, which together with the slow turn-over of mature LC limits repair of the network. Furthermore, replenishment of the LC network leads to constitutive entry of cells into the epidermal compartment. Thus, immune injury triggers functional adaptation of mechanisms used to maintain tissue-resident macrophages at other sites, but this process is highly inefficient in the skin. Highlights Immune injury leads to recruitment of a single wave of monocytes to replace resident Langerhans cells (LC). DC lineage cells cannot become long-term replacement LC. The size of the re-emerging network is controlled by density-dependent division of mature LC. Immune injury and inefficient repopulation by monocyte-derived cells lead to a permanently altered LC niche.

show abstract

Multiomics Investigation Revealing the Characteristics of HIV-1-Infected Cells In Vivo

Aso

¹

,

Nagaoka

²

,

Kawakami

³

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

Cbfβ2 deficiency preserves Langerhans cell precursors by lack of selective TGFβ receptor signaling

Abstract: Tenno et al. show that loss of Cbfβ2, one of two RNA splice variants of the Cbfb gene, results in the persistence of embryonic Langerhans cell precursors in the adult epidermis by selective loss of BMP7-BMPR1A signaling with intact TGFβR1 signaling.

Cited by 19 publications

References 43 publications

Osteoprotegerin-dependent M cell self-regulation balances gut infection and immunity

Osteoprotegerin-dependent M cell self-regulation balances gut infection and immunity

A single wave of monocytes is sufficient to replenish the long-term Langerhans cell network after immune injury

Multiomics Investigation Revealing the Characteristics of HIV-1-Infected Cells In Vivo

Contact Info

Product

Resources

About