Foxp3⁺ regulatory T cells ensure B lymphopoiesis by inhibiting the granulopoietic activity of effector T cells in mouse bone marrow

Abstract

Foxp3 + Treg cells are crucial for maintaining T-cell homeostasis, but their role in B-cell homeostasis remains unclear. Here, we found that Foxp3 mutant scurfy mice had fewer B-lineage cells and progenitors, including common lymphoid progenitors and lymphoidprimed multipotent progenitors, but higher myeloid-lineage cell numbers in BM compared with WT littermates. Homeostasis within the HSC compartment was also compromised with apparent expansion of long-and short-term HSCs. This abnormality was due to the lack of Treg cells, but not to the Treg-cell extrinsic functions of Foxp3 or cellautonomous defects. Among cytokines enriched in the BM of scurfy mice, IFN-γ affected only B lymphopoiesis, but GM-CSF, TNF, and IL-6 collectively promoted granulopoiesis at the expense of B lymphopoiesis. Neutralization of these three cytokines reversed the hematopoietic defects on early B-cell progenitors in scurfy mice. Treg cells ensured B lymphopoiesis by reducing the production of these cytokines by effector T cells, but not by directly affecting B lymphopoiesis. These results suggest that Treg cells occupy an important niche in the BM to protect B-lineage progenitor cells from excessive exposure to a lymphopoiesis-regulating milieu.Keywords: B lymphopoiesis r Foxp3 r Granulopoietins r Hematopoiesis r Regulatory T cells Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction CD4 + Foxp3 + Treg cells are essential for maintaining immune homeostasis, as evidenced by the severe autoimmune lymphoproliferative disease observed in Treg-cell-deficient mice and humans [1,2]. Treg cells were initially identified in the secondary lymphoid tissues where they suppress the initial priming and Correspondence: Prof. Jeehee Youn e-mail: jhyoun@hanyang.ac.kr effector differentiation of autoreactive T cells [3]. They function by directly suppressing T cells and/or interacting with DCs to limit their ability to prime T cells effectively [4,5]. In addition to their constitutive presence in secondary lymphoid tissues, Treg cells have been found in several nonlymphoid sites, such as mucosal tissue, skin, liver, and lung, during inflammation as well as in steady-state conditions [6][7][8][9][10]. These Treg cells appear to regulate * These authors contributed equally to this work. * * These senior authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 168Sunghoon Kim et al. Eur. J. Immunol. 2015. 45: 167-179 tissue-tropic autoimmunity and inflammation, and alter pathogen clearance during peripheral infection. A diverse array of adhesion molecules and chemokine receptors that are expressed on Treg cells seem to license them to migrate to peripheral tissues. A fraction of Treg cells have been shown to express the BM homing receptor CXCR4 [11], suggesting the existence of a niche for Treg cells in the BM. Indeed, there are studies showing that healthy human BM contains a substantial number of Treg cells that traffic via CXC...

Early Growth Response-1 Plays a Non-redundant Role in the Differentiation of B Cells into Plasma Cells

“…Splenic single-cell suspensions from WT and Egr1 -/- mice were stained and analyzed using a FACS Canto II (BD Biosciences) as described previously ( 14 ). The following mAbs and reagents were purchased from BD Biosciences or eBioscience: anti-GL7-FITC, anti-CD4-PE, anti-B220-PerCP, anti-CD11C-allophycocyanin, anti-CD138-allophycocyanin, 7-AAD, and Annexin V-FITC.…”

Bone Marrow T Cells and the Integrated Functions of Recirculating and Tissue-Resident Memory T Cells

“…Surprisingly, the maintenance of normal bone mass and bone mineral density in physiological conditions is promoted by T cells, which stimulate the production of the RANK-L decoy receptor osteoprotegerin by B cells, through CD40L/CD40 interaction ( 93 ). A cross-talk between T cells and hematopoietic precursors occurs in the BM in normal healthy conditions ( 94 , 95 ). For example, it has been shown that BM T cells sustain normal granulopoiesis ( 94 ), while regulatory T cells inhibit excessive T cell-production of the granulopoiesis-promoting cytokines GM-CSF, TNF, and IL-6, thus allowing for sufficient B lymphopoiesis ( 95 ).…”

Regulatory T cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease

“…B cell-deficient scurfy mice have less chronic inflammation and prolonged survival, and B cell transfer into these mice restores autoimmunity [ 6 ]. Interestingly, in the bone marrow, scurfy mice have fewer B cells and higher numbers of cells of the myeloid lineage as compared with wild-type (WT) littermates [ 7 , 8 ]. In a recent publication it was shown that these effects depend on granulopoietic effector cytokines (granulocyte macrophage colony-stimulating factor, tumor necrosis factor, interleukin 6 (IL-6)) and that Tregs do not directly affect B lymphopoiesis, but that they reduce the production of granulopoietic cytokines by suppressing the respective T eff cells [ 7 ].…”