Lkb1 Loss in Regulatory T Cells Leads to Dysregulation of Hematopoietic Stem Cell Expansion and Differentiation in Bone Marrow

Overview

Journal FEBS Open Bio

Specialty Biology

Date 2022 Dec 14

PMID 36515008

Authors

Jiadi Chen

Jingru Liu

Huifang Huang

Affiliations

Soon will be listed here.

Abstract

The tumor suppressor Lkb1 is known to regulate the expression of forkhead box P3 (Foxp3), thereby maintaining the levels of Foxp3 regulatory T cells (Treg) that play a crucial role in self-tolerance. However, the effect of Lkb1 in Treg on hematopoietic stem cells (HSCs) in the bone marrow (BM) remains obscure. Here, we demonstrated that conditional deletion of Lkb1 in Treg causes loss of Treg in the BM, which leads to failure of HSC homeostasis and the abnormal expansion. Moreover, the loss of BM Treg results in dysregulation of other developing progenitors/stem cell populations, leading to the defective differentiation of T cells and B cells. In addition, HSC from the BM with Treg loss exhibited poor engraftment efficiency, indicating that loss of Treg leads to irreversible impairment of HSC. Collectively, these results demonstrated the essential role of Lkb1 in Treg for maintaining HSC homeostasis and differentiation in mice. These findings provide insight into the mechanisms of HSC regulation and guidance for a strategy to improve the outcomes and reduce complications of HSC transplantation.

Citing Articles

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PMID: 39367881 PMC: 11456083. DOI: 10.1007/s00018-024-05445-3.

References

Coelho A, Schaller M, Benjamim C, Orlofsky A, Hogaboam C, Kunkel S . The chemokine CCL6 promotes innate immunity via immune cell activation and recruitment. J Immunol. 2007; 179(8):5474-82. DOI: 10.4049/jimmunol.179.8.5474. View

Wculek S, Sancho D . LKB1 restrains dendritic cell function. Cell Res. 2019; 29(6):429-431. PMC: 6796839. DOI: 10.1038/s41422-019-0169-0. View

Zhang C, Yi W, Li F, Du X, Wang H, Wu P . Eosinophil-derived CCL-6 impairs hematopoietic stem cell homeostasis. Cell Res. 2018; 28(3):323-335. PMC: 5835778. DOI: 10.1038/cr.2018.2. View

Watkins B, Tkachev V, Furlan S, Hunt D, Betz K, Yu A . CD28 blockade controls T cell activation to prevent graft-versus-host disease in primates. J Clin Invest. 2018; 128(9):3991-4007. PMC: 6118599. DOI: 10.1172/JCI98793. View

Agle K, Vincent B, Piper C, Belle L, Zhou V, Shlomchik W . Bim regulates the survival and suppressive capability of CD8 FOXP3 regulatory T cells during murine GVHD. Blood. 2018; 132(4):435-447. PMC: 6071561. DOI: 10.1182/blood-2017-09-807156. View

Muller A, Poyser J, Kupper N, Burnett C, Ko R, Kohrt H . Donor hematopoiesis in mice following total lymphoid irradiation requires host T-regulatory cells for durable engraftment. Blood. 2014; 123(18):2882-92. PMC: 4007614. DOI: 10.1182/blood-2013-10-530212. View

Wang Y, Du X, Wei J, Long L, Tan H, Guy C . LKB1 orchestrates dendritic cell metabolic quiescence and anti-tumor immunity. Cell Res. 2019; 29(5):391-405. PMC: 6796952. DOI: 10.1038/s41422-019-0157-4. View

Pelgrom L, Patente T, Sergushichev A, Esaulova E, Otto F, Ozir-Fazalalikhan A . LKB1 expressed in dendritic cells governs the development and expansion of thymus-derived regulatory T cells. Cell Res. 2019; 29(5):406-419. PMC: 6796856. DOI: 10.1038/s41422-019-0161-8. View

Li X, Liang Y, Leblanc M, Benner C, Zheng Y . Function of a Foxp3 cis-element in protecting regulatory T cell identity. Cell. 2014; 158(4):734-748. PMC: 4151505. DOI: 10.1016/j.cell.2014.07.030. View

10.

Wu D, Luo Y, Guo W, Niu Q, Xue T, Yang F . Lkb1 maintains T cell lineage identity. Nat Commun. 2017; 8:15876. PMC: 5481770. DOI: 10.1038/ncomms15876. View

11.

Ukena S, Velaga S, Geffers R, Grosse J, Baron U, Buchholz S . Human regulatory T cells in allogeneic stem cell transplantation. Blood. 2011; 118(13):e82-92. DOI: 10.1182/blood-2011-05-352708. View

12.

Hu X, Garcia M, Weng L, Jung X, Murakami J, Kumar B . Identification of a common mesenchymal stromal progenitor for the adult haematopoietic niche. Nat Commun. 2016; 7:13095. PMC: 5062560. DOI: 10.1038/ncomms13095. View

13.

Challen G, Boles N, Chambers S, Goodell M . Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1. Cell Stem Cell. 2010; 6(3):265-78. PMC: 2837284. DOI: 10.1016/j.stem.2010.02.002. View

14.

Liu Z, Zhu H, Dai X, Wang C, Ding Y, Song P . Macrophage Liver Kinase B1 Inhibits Foam Cell Formation and Atherosclerosis. Circ Res. 2017; 121(9):1047-1057. PMC: 5640502. DOI: 10.1161/CIRCRESAHA.117.311546. View

15.

Thornton A, Korty P, Tran D, Wohlfert E, Murray P, Belkaid Y . Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol. 2010; 184(7):3433-41. PMC: 3725574. DOI: 10.4049/jimmunol.0904028. View

16.

Ganguly S, Ross D, Panoskaltsis-Mortari A, Kanakry C, Blazar B, Levy R . Donor CD4+ Foxp3+ regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice. Blood. 2014; 124(13):2131-41. PMC: 4186542. DOI: 10.1182/blood-2013-10-525873. View

17.

Nagasawa T . Microenvironmental niches in the bone marrow required for B-cell development. Nat Rev Immunol. 2006; 6(2):107-16. DOI: 10.1038/nri1780. View

18.

Yang K, Blanco D, Neale G, Vogel P, Avila J, Clish C . Homeostatic control of metabolic and functional fitness of T cells by LKB1 signalling. Nature. 2017; 548(7669):602-606. PMC: 5804356. DOI: 10.1038/nature23665. View

19.

Hirata Y, Kakiuchi M, Robson S, Fujisaki J . CD150 CD4 T cells and CD150 regulatory T cells regulate hematopoietic stem cell quiescence via CD73. Haematologica. 2018; 104(6):1136-1142. PMC: 6545860. DOI: 10.3324/haematol.2018.198283. View

20.

Du J, Paz K, Thangavelu G, Schneidawind D, Baker J, Flynn R . Invariant natural killer T cells ameliorate murine chronic GVHD by expanding donor regulatory T cells. Blood. 2017; 129(23):3121-3125. PMC: 5465838. DOI: 10.1182/blood-2016-11-752444. View