mTORC1 and mTORC2 Kinase Signaling and Glucose Metabolism Drive Follicular Helper T Cell Differentiation

Zeng, Hu; Cohen, Sivan; Guy, Cliff; Shrestha, Sharad; Neale, Geoffrey; Brown, Scott A.; Cloer, Caryn; Kishton, Rigel J.; Gao, Xia; Youngblood, Benjamin A.; Do, Mytrang; Li, Ming O.; Locasale, Jason W.; Rathmell, Jeffrey C.; Chi, Hongbo

doi:10.1016/j.immuni.2016.08.017

Cited by 289 publications

(349 citation statements)

References 45 publications

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“…Although previous studies 11 have suggested that Tfh, like Treg, utilize less glycolysis, mitochondrial respiration and as a consequence, mTOR function than Th1 cells, AZD2014 and RAPA both suppressed Tfh effectively. This is consistent with recent data 48 demonstrating that glucose metabolism and both mTORC1 and mTORC2 signaling are essential for Tfh differentiation and GC reaction in Peyer’s patches. In the latter study, mTORC2 was uniquely required for normal Tfh cell localization in PP, expression of Forkhead box protein 01 (Fox01) targets and nuclear exclusion of Fox01 upon inducible T cell costimulator ligation.…”

Section: Discussionsupporting

confidence: 94%

Influence of the Novel ATP-Competitive Dual mTORC1/2 Inhibitor AZD2014 on Immune Cell Populations and Heart Allograft Rejection

et al. 2017

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Background Little is known about how new generation adenosine triphosphate (ATP)-competitive mechanistic target of rapamycin (mTOR) kinase inhibitors (TORKinibs) affect immunity and allograft rejection. Methods mTOR complex (C) 1 and 2 signaling in dendritic cells (DC) and T cells was analyzed by Western blotting, while immune cell populations in normal and heart allograft recipient mice were analyzed by flow cytometry. Alloreactive T cell proliferation was quantified in MLR; intracellular cytokine production and serum antidonor IgG levels were determined by flow analysis and immunofluorescence staining used to detect IgG in allografts. Results The novel TORKinib AZD2014 impaired DC differentiation and T cell proliferation in vitro and depressed immune cells and allospecific T cell responses in vivo. A 9-day course of AZD2014 (10 mg/kg ip twice daily) or rapamycin (RAPA; 1mg/kg ip daily) prolonged median heart allograft survival time significantly (25 days for AZD2014; 100 days for RAPA; 9.5 days for control). Like RAPA, AZD2014 suppressed graft mononuclear cell infiltration, increased regulatory T cell (Treg) to effector memory T cell (Tem) ratios and reduced T follicular helper (Tfh) and B cells 7 days posttransplant. By 21 days (10 days after drug withdrawal), however, Tfh and B cells and donor-specific IgG1 and IgG2c antibody titers were significantly lower in RAPA- compared with AZD2014-treated mice. Elevated Treg to Tem ratios were maintained after RAPA, but not AZD2014 withdrawal. Conclusions Immunomodulatory effects of AZD2014, unlike those of RAPA, were not sustained after drug withdrawal, possibly reflecting distinct pharmacokinetics or/and inhibitory effects of AZD2014 on mTORC2.

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Section: Discussionsupporting

confidence: 94%

Influence of the Novel ATP-Competitive Dual mTORC1/2 Inhibitor AZD2014 on Immune Cell Populations and Heart Allograft Rejection

et al. 2017

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“…In contrast, recent studies using conditional knockout mice showed that mTORC1 signaling was essential for induction of Tfh responses (30,31). These contradictory results may be explained by the different approaches used to silence mTOR activity.…”

Section: Discussionmentioning

confidence: 92%

mTOR Promotes Antiviral Humoral Immunity by Differentially Regulating CD4 Helper T Cell and B Cell Responses

Lee

et al. 2017

J Virol

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mTOR has important roles in regulation of both innate and adaptive immunity, but whether and how mTOR modulates humoral immune responses have yet to be fully understood. To address this issue, we examined the effects of rapamycin, a specific inhibitor of mTOR, on B cell and CD4 T cell responses during acute infection with lymphocytic choriomeningitis virus. Rapamycin treatment resulted in suppression of virus-specific B cell responses by inhibiting proliferation of germinal center (GC) B cells. In contrast, the number of memory CD4 T cells was increased in rapamycin-treated mice. However, the drug treatment caused a striking bias of CD4 T cell differentiation into Th1 cells and substantially impaired formation of follicular helper T (Tfh) cells, which are essential for humoral immunity. Further experiments in which mTOR signaling was modulated by RNA interference (RNAi) revealed that B cells were the primary target cells of rapamycin for the impaired humoral immunity and that reduced Tfh formation in rapamycin-treated mice was due to lower GC B cell responses that are essential for Tfh generation. Additionally, we found that rapamycin had minimal effects on B cell responses activated by lipopolysaccharide (LPS), which stimulates B cells in an antigen-independent manner, suggesting that rapamycin specifically inhibits B cell responses induced by B cell receptor stimulation with antigen. Together, these findings demonstrate that mTOR signals play an essential role in antigen-specific humoral immune responses by differentially regulating B cell and CD4 T cell responses during acute viral infection and that rapamycin treatment alters the interplay of immune cell subsets involved in antiviral humoral immunity.IMPORTANCE mTOR is a serine/threonine kinase involved in a variety of cellular activities. Although its specific inhibitor, rapamycin, is currently used as an immunosuppressive drug in transplant patients, it has been reported that rapamycin can also stimulate pathogen-specific cellular immunity in certain circumstances. However, whether and how mTOR regulates humoral immunity are not well understood. Here we found that rapamycin treatment predominantly inhibited GC B cell responses during viral infection and that this led to biased helper CD4 T cell differentiation as well as impaired antibody responses. These findings suggest that inhibition of B cell responses by rapamycin may play an important role in regulation of allograft-specific antibody responses to prevent organ rejection in transplant recipients. Our results also show that consideration of antibody responses is required in cases where rapamycin is used to stimulate vaccine-induced immunity.

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“…In contrast, in Th1 cells mTORC2 has been reported to signal through Akt (Lee et al, 2010). In contrast to the situation for Th1 and Th17 cells, which exert their functions primarily within non-lymphoid tissues and which rely on one or other of the mTOR complexes for their differentiation, Tfh cells, which are restricted to germinal centers in secondary lymphoid organs, are dependent on both mTORC1 and mTORC2, since Tnfrsf4-cre -mediated deletion of Raptor or Rictor is sufficient to prevent their development (Zeng et al, 2016). …”

Section: Mtor In the Adaptive Immune Systemmentioning

confidence: 99%

MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells

2017

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Tissue-resident immune cells must balance survival in peripheral tissues with the capacity to respond rapidly upon infection or tissue damage, and in turn couple these responses with intrinsic metabolic control and conditions in the tissue microenvironment. The serine/threonine kinase mammalian/mechanistic target of rapamycin (mTOR) is a central integrator of extracellular and intracellular growth signals and cellular metabolism and plays important roles in both innate and adaptive immune responses. This review discusses the function of mTOR signaling in the differentiation and function of tissue-resident immune cells, with focus on the role of mTOR as a metabolic sensor and its impact on metabolic regulation in innate and adaptive immune cells. We also discuss the impact of metabolic constraints in tissues on immune homeostasis and disease, and how manipulating mTOR activity with drugs such as rapamycin can modulate immunity in these contexts.

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mTORC1 and mTORC2 Kinase Signaling and Glucose Metabolism Drive Follicular Helper T Cell Differentiation

Cited by 289 publications

References 45 publications

Influence of the Novel ATP-Competitive Dual mTORC1/2 Inhibitor AZD2014 on Immune Cell Populations and Heart Allograft Rejection

Influence of the Novel ATP-Competitive Dual mTORC1/2 Inhibitor AZD2014 on Immune Cell Populations and Heart Allograft Rejection

mTOR Promotes Antiviral Humoral Immunity by Differentially Regulating CD4 Helper T Cell and B Cell Responses

MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells

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