mTORC2 in Thymic Epithelial Cells Controls Thymopoiesis and T Cell Development

Wang, Hongxia; Cheng, Joyce; Chu, Shuai; Qiu, Yurong; Zhong, Xiao‐Ping

doi:10.4049/jimmunol.1502698

Cited by 13 publications

(18 citation statements)

References 54 publications

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“…The thymic micro-environment plays a critical role in enabling the appropriate development of nascent T cells, particularly thymic epithelial cells (TECs). Selective Rictor −/− in TECs results in a reduction in thymic mass and cellularity of TECs, and decreased generation of specific T cell lineages: TCRαβ, TCRγδ, invariant NKT [ 84 ] and regulatory T cells, thereby revealing an important role of mTORC2 in thymopoiesis and T cell lineage generation [ 85 ].…”

Section: Role Of Mtor Signalling In Haemopoiesismentioning

confidence: 99%

The role of mTOR-mediated signals during haemopoiesis and lineage commitment

Malik

Sansom

Michie

2018

Biochemical Society Transactions

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The serine/threonine protein kinase mechanistic target of rapamycin (mTOR) has been implicated in the regulation of an array of cellular functions including protein and lipid synthesis, proliferation, cell size and survival. Here, we describe the role of mTOR during haemopoiesis within the context of mTORC1 and mTORC2, the distinct complexes in which it functions. The use of conditional transgenic mouse models specifically targeting individual mTOR signalling components, together with selective inhibitors, have generated a significant body of research emphasising the critical roles played by mTOR, and individual mTOR complexes, in haemopoietic lineage commitment and development. This review will describe the profound role of mTOR in embryogenesis and haemopoiesis, underscoring the importance of mTORC1 at the early stages of haemopoietic cell development, through modulation of stem cell potentiation and self-renewal, and erythroid and B cell lineage commitment. Furthermore, the relatively discrete role of mTORC2 in haemopoiesis will be explored during T cell development and B cell maturation. Collectively, this review aims to highlight the functional diversity of mTOR signalling and underline the importance of this pathway in haemopoiesis.

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Section: Role Of Mtor Signalling In Haemopoiesismentioning

confidence: 99%

The role of mTOR-mediated signals during haemopoiesis and lineage commitment

Malik

Sansom

Michie

2018

Biochemical Society Transactions

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“…We have previously shown that the TSC1-MTOR signaling axis controls macrophage polarization [25]. Very recently, by deletion of either Rptor or Rictor in TECs, it has been shown that either of MTORC1 or MTORC2 signaling is important for thymopoiesis and proper generation of multiple T cell lineages [26,27]. However, how MTORC1 and MTORC2 together affect TEC differentiation and the underlying molecular mechanisms are unknown.…”

Section: Introductionmentioning

confidence: 99%

MTOR signaling is essential for the development of thymic epithelial cells and the induction of central immune tolerance

Liang

Zhang

et al. 2018

Autophagy

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Thymic epithelial cells (TECs) are critical for the establishment and maintenance of appropriate microenvironment for the positive and negative selection of thymocytes and the induction of central immune tolerance. Yet, little about the molecular regulatory network on TEC development and function is understood. Here, we demonstrate that MTOR (mechanistic target of rapamycin [serine/threonine kinase]) is essential for proper development and functional maturation of TECs. Pharmacological inhibition of MTOR activity by rapamycin (RPM) causes severe thymic atrophy and reduction of TECs. TEC-specific deletion of Mtor causes the severe reduction of mTECs, the blockage of thymocyte differentiation and output, the reduced generation of thymic regulatory T (Treg) cells and the impaired expression of tissue-restricted antigens (TRAs) including Fabp2, Ins1, Tff3 and Chrna1 molecules. Importantly, specific deletion of Mtor in TECs causes autoimmune diseases characterized by enhanced tissue immune cell infiltration and the presence of autoreactive antibodies. Mechanistically, Mtor deletion causes overdegradation of CTNNB1/Beta-Catenin due to excessive autophagy and the attenuation of WNT (wingless-type MMTV integration site family) signaling in TECs. Selective inhibition of autophagy significantly rescued the poor mTEC development caused by Mtor deficiency. Altogether, MTOR is essential for TEC development and maturation by regulating proliferation and WNT signaling activity through autophagy. The present study also implies that long-term usage of RPM might increase the risk of autoimmunity by impairing TEC maturation and function.

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“…In T cells, the PI3K/Akt, RasGRP1/Ras/Erk, and PKCθ-CARMA1 pathways are critical for TCR-induced mTORC1 and mTORC2 activation ( Gorentla et al, 2011 ; Hamilton et al, 2014 ). mTOR and its tight regulation are pivotal for proper T cell activation ( Chi, 2012 ; O'Brien et al, 2012 ; O'Brien et al, 2011 ; Wu et al, 2011 ; Yang et al, 2011 ), Th1/2/17 differentiation ( Delgoffe et al, 2011 ; Lee et al, 2010 ; Zhang et al, 2012 ), effector/memory CD8 T cell differentiation ( Araki et al, 2009 ; Rao et al, 2010 ), Treg function ( Park et al, 2013 ; Zeng et al, 2013 ), and iNKT maturation and effector lineage differentiation ( Wu et al, 2014 ; Wu et al, 2014 ; Shin et al, 2014 ; Wei et al, 2014 ; Yang et al, 2015 ; Prevot et al, 2015 ; Zhang et al, 2014 ), and extrinsic control of intrathymic αβ T and γδ T cell development ( Wang et al, 2016 ; Wang et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Critical roles of mTOR Complex 1 and 2 for T follicular helper cell differentiation and germinal center responses

Yang

Lin

Pan

et al. 2016

eLife

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104

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T follicular helper (Tfh) cells play critical roles for germinal center responses and effective humoral immunity. We report here that mTOR in CD4 T cells is essential for Tfh differentiation. In Mtorf/f-Cd4Cre mice, both constitutive and inducible Tfh differentiation is severely impaired, leading to defective germinal center B cell formation and antibody production. Moreover, both mTORC1 and mTORC2 contribute to Tfh and GC B cell development but may do so via distinct mechanisms. mTORC1 mainly promotes CD4 T cell proliferation to reach the cell divisions necessary for Tfh differentiation, while Rictor/mTORC2 regulates Tfh differentiation by promoting Akt activation and TCF1 expression without grossly influencing T cell proliferation. Together, our results reveal crucial but distinct roles for mTORC1 and mTORC2 in CD4 T cells during Tfh differentiation and germinal center responses.DOI: http://dx.doi.org/10.7554/eLife.17936.001

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mTORC2 in Thymic Epithelial Cells Controls Thymopoiesis and T Cell Development

Cited by 13 publications

References 54 publications

The role of mTOR-mediated signals during haemopoiesis and lineage commitment

The role of mTOR-mediated signals during haemopoiesis and lineage commitment

MTOR signaling is essential for the development of thymic epithelial cells and the induction of central immune tolerance

Critical roles of mTOR Complex 1 and 2 for T follicular helper cell differentiation and germinal center responses

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