Foxp3+ regulatory T cells maintain the bone marrow microenvironment for B cell lymphopoiesis

Pierini, Antonio; Nishikii, Hidekazu; Baker, Jeanette; Kimura, Takaharu; Kwon, Hye-Sook; Pan, Yuqiong; Chen, Yan; Álvarez, Maite; Strober, William; Velardi, Andrea; Shizuru, Judith A.; Wu, Joy Y.; Chiba, Shigeru; Negrin, Robert S.

doi:10.1038/ncomms15068

Cited by 73 publications

(83 citation statements)

References 41 publications

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“…Previous reports have suggested that immune tolerance may exist in the BM niche secondary to the presence of T regs . 35,36 Activation and proliferation of T cons in an aGVHD model can be prevented by in vivo expansion of potent T regs using activation of TNF superfamily receptor TNFRSF25 (also termed DR3). Expansion of donor T regs can be achieved by injection of either a single dose of agonistic anti-DR3 mAb (4C12) 37,38 or TL1A-Ig fusion protein along with lowdose IL-2.…”

Section: Donor T Cells Are Critical To Impaired B-cell Developmentmentioning

confidence: 99%

Impaired bone marrow B-cell development in mice with a bronchiolitis obliterans model of cGVHD

Kolupaev¹,

Dant²,

Bommiasamy³

et al. 2018

Blood Advances

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Chronic graft-versus-host disease (cGVHD) causes significant morbidity and mortality in patients after allogeneic bone marrow (BM) or stem cell transplantation (allo-SCT). Recent work has indicated that both T and B lymphocytes play an important role in the pathophysiology of cGVHD. Previously, our group showed a critical role for the germinal center response in the function of B cells using a bronchiolitis obliterans (BO) model of cGVHD. Here, we demonstrated for the first time that cGVHD is associated with severe defects in the generation of BM B lymphoid and uncommitted common lymphoid progenitor cells. We found an increase in the number of donor CD4 T cells in the BM of mice with cGVHD that was negatively correlated with B-cell development and the frequency of osteoblasts and Prrx-1-expressing perivascular stromal cells, which are present in the B-cell niche. Use of anti-DR3 monoclonal antibodies to enhance the number of donor regulatory T cells (T) in the donor T-cell inoculum ameliorated the pathology associated with BO in this model. This correlated with an increased number of endosteal osteoblastic cells and significantly improved the generation of B-cell precursors in the BM after allo-SCT. Our work indicates that donor T play a critical role in preserving the generation of B-cell precursors in the BM after allo-SCT. Approaches to enhance the number and/or function of donor T that do not enhance conventional T-cell activity may be important to decrease the incidence and severity of cGVHD in part through normal B-cell lymphopoiesis.

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Section: Donor T Cells Are Critical To Impaired B-cell Developmentmentioning

confidence: 99%

Impaired bone marrow B-cell development in mice with a bronchiolitis obliterans model of cGVHD

Kolupaev¹,

Dant²,

Bommiasamy³

et al. 2018

Blood Advances

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“…[57][58][59] Only until recently, the presence of Tregs and their potential roles in various non-lymphoid tissues of both mice and humans has been documented, such as bone marrow, skin, intestinal mucosa, lung, liver, adipose tissue, grafts, placenta, muscle, and various tumors. [60][61][62][63][64][65][66] These tissue-resident Tregs are believed to be significantly differed from Tregs in secondary lymphoid organs since they experience a tissue-specific environment and successively acquire a unique gene expression programing including transcription factors, suppressive regulatory molecules, homing receptors, and metabolic adaptation. 55 The investigation of unique transcriptome and metabolome presenting by tissue-associated Treg might provide a variety of therapeutic interventions to immunologically mediated disorders by specifically targeting resident Tregs ( Figure 2).…”

Section: The De Velopment and Fun C Ti On S Of Tissue-re S Ident Trmentioning

confidence: 99%

“…Physiological IL-7 produced by a subpopulation of ICAM1+ perivascular stromal cells existing in specific bone marrow environment sustains normal B-cell differentiation, which is shown controlled by environmental Tregs. 60 Yet, the underline mechanism of unique function of Tregs in the bone marrow is not entirely investigated, and a Treg subpopulation expressed a hematopoietic stem cell marker, CD150, was described to protect hematopoietic stem cells (HSCs) from oxidative stress and maintaining their quiescence by generating adenosine within HSC niche in the bone marrow. 68 Meanwhile, recent study shows that certain Treg development also requires re-presentation by bone marrow derived antigen-presenting cells, indicating a bone marrow participation in Treg development.…”

Section: Bone Marrowmentioning

confidence: 99%

Metabolic adaptation orchestrates tissue context‐dependent behavior in regulatory T cells

Wang

2020

Immunological Reviews

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Immunological Reviews. 2020;295:126-139. wileyonlinelibrary.com/journal/imr | INTRODUC TI ONThe immune system is mainly responsible for protecting individuals from pathogen invasion. Meanwhile, the immune system also actively participates in tissue repairing and homeostasis, which are critical for the avoidance of autoimmunity. A subset of CD4 + T cells, which is characterized by the expression of the master transcription factor forkhead box protein P3 (Foxp3) and known as regulatory T cells (Tregs), is the major immune subset to maintain the immune homeostasis. 1-4 The importance of Tregs on governing peripheral tissue and immune homeostasis is validated by observations in both human patients and murine models. In humans, the mutations in Foxp3 result in impaired development and dysfunction of Tregs and cause immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, characterized by multiple autoimmune disorders. 5,6 Mice carrying dysfunctional Foxp3, known as scurfy mice, are deficient in Abstract The diverse distribution and functions of regulatory T cells (Tregs) ensure tissue and immune homeostasis; however, it remains unclear which factors can guide distribution, local differentiation, and tissue context-specific behavior in Tregs. Although the emerging concept that Tregs could re-adjust their transcriptome based on their habitations is supported by recent findings, the underlying mechanisms that reprogram transcriptome in Tregs are unknown. In the past decade, metabolic machineries have been revealed as a new regulatory circuit, known as immunometabolic regulation, to orchestrate activation, differentiation, and functions in a variety of immune cells, including Tregs. Given that systemic and local alterations of nutrient availability and metabolite profile associate with perturbation of Treg abundance and functions, it highlights that immunometabolic regulation may be one of the mechanisms that orchestrate tissue context-specific regulation in Tregs. The understanding on how metabolic program instructs Tregs in peripheral tissues not only represents a critical opportunity to delineate a new avenue in Treg biology but also provides a unique window to harness Treg-targeting approaches for treating cancer and autoimmunity with minimizing side effects. This review will highlight the metabolic features on guiding Treg formation and function in a disease-oriented perspective and aim to pave the foundation for future studies. K E Y W O R D S autoimmunity, cancer, immunometabolism, inflammation, metabolic adaptation, regulatory T cell | 127 WANG et Al.

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“…These long‐lived cells migrate into the BM through the CXCL12/CXCR4 axis forming a Treg cell reservoir . In the BM, Treg cells have been shown not only to regulate the niche compartment – and thereby influence B‐cell differentiation – but also to support maintenance of long‐lived plasma cells . Interestingly, a recent report suggests that niche Treg cells may be distinct from peripheral Treg cells by their high expression of the HSC marker CD150 and their capacity to release adenosine into their local environment, which in turn reduces oxidative stress in HSC .…”

Section: Fatty Acids In the Bone Marrow To Support Long‐lived Immune mentioning

confidence: 99%

“…48 In the BM, Treg cells have been shown not only to regulate the niche compartmentand thereby influence B-cell differentiationbut also to support maintenance of long-lived plasma cells. 49,50 Interestingly, a recent report suggests that niche Treg cells may be distinct from peripheral Treg cells by their high expression of the HSC marker CD150 and their capacity to release adenosine into their local environment, which in turn reduces oxidative stress in HSC. 51 However, studies so far have not investigated whether the BM stroma contributes to Treg cell metabolism by provision of free fatty acids as described in peripheral tissues.…”

Section: Fatty Acids In the Bone Marrow To Support Long-lived Immune mentioning

confidence: 99%

Local exchange of metabolites shapes immunity

2018

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SummaryImmune cell differentiation and function depend on metabolic changes for the provision of energy and metabolites. Consequently, cellular metabolism relies on the availability of micronutrients such as vitamins and energy‐rich sources including amino acids and fatty acids. The bone marrow controls the continuous production of blood cells and is thereby reliant on the sophisticated interplay of progenitor and mature immune cells with its stromal microenvironment. The significance of stromal subsets in immunopoiesis is undisputed; however, our current knowledge is limited to their role in the production and secretion of a variety of soluble proteins such as cytokines. In contrast, the role of the haematopoietic niche in controlling and providing nutrients such as fatty acids, amino acids and vitamins, which are required for immune cell differentiation and function, remains largely elusive. In this review, we summarize the current understanding of local nutritional exchange and control between immune and stromal cells in peripheral tissue and, when it is known, in the bone marrow. The parallels found between peripheral tissues and bone marrow stroma raises the question of how local metabolism is capable of influencing haematopoiesis and immunopoiesis. A better understanding of the local exchange of nutrients in the bone marrow can be used to improve immune cell formation during ageing, after haematopoietic stem cell transplantation and during immune challenge.

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Foxp3+ regulatory T cells maintain the bone marrow microenvironment for B cell lymphopoiesis

Cited by 73 publications

References 41 publications

Impaired bone marrow B-cell development in mice with a bronchiolitis obliterans model of cGVHD

Impaired bone marrow B-cell development in mice with a bronchiolitis obliterans model of cGVHD

Metabolic adaptation orchestrates tissue context‐dependent behavior in regulatory T cells

Local exchange of metabolites shapes immunity

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