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

Yang, Jialong; Lin, Xingguang; Pan, Yun; Wang, Jinli; Chen, Pengcheng; Huang, Haihong; Xue, Hai-Hui; Gao, Jimin; Zhong, Xiao‐Ping

doi:10.7554/elife.17936

Cited by 92 publications

(108 citation statements)

References 79 publications

(100 reference statements)

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“…Rescue of the rapamycin phenotype when only transferred B cells carried the Mtor F2108L mutation confirmed that mTORC1 was required in a B cell-specific manner, rather than acting through other relevant cell types that rely on this pathway for differentiation and function, such as Tfh cells (Ray et al, 2015; Yang et al, 2016; Zeng et al, 2016). We expect that this chemical-genetics approach, and the Mtor F2108L mice in particular, will be useful to others to address the roles of mTORC1 in other settings, without the kinetic limitations of conditional mouse genetics.…”

Section: Discussionmentioning

confidence: 89%

Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase

et al. 2017

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SUMMARY During antibody affinity maturation, germinal center (GC) B cells cycle between affinity-driven selection in the light zone (LZ) and proliferation and somatic hypermutation in the dark zone (DZ). Although selection of GC B cells is triggered by antigen-dependent signals delivered in the LZ, DZ proliferation occurs in the absence of such signals. We show that positive selection triggered by T cell help activates the mechanistic target of rapamycin complex 1 (mTORC1), which promotes the anabolic program that supports DZ proliferation. Blocking mTORC1 prior to growth prevented clonal expansion, whereas blockade after cells reached peak size had little to no effect. Conversely, constitutively active mTORC1 led to DZ enrichment but loss of competitiveness and impaired affinity maturation. Thus, mTORC1 activation is required for fueling B cells prior to DZ proliferation rather than for allowing cell cycle progression itself, and must be regulated dynamically during cyclic re-entry to ensure efficient affinity-based selection.

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Section: Discussionmentioning

confidence: 89%

Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase

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: 89%

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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“…9 In humans, IL-12, IL-6, and TGFβ have been implicated in Tfh cell development. 49,50 This distinct mode of metabolic reprogramming may stem from the need for fully differentiated Tfh cells to survive in the GC, where glucose may become limiting due to the extensive proliferation undergone by GC B cells. 27,28 Unlike mouse Tfh cells, in which development is inhibited by TGFβ, 29 human TGFβ is found to synergize with IL-12 and IL-23, which also signals through STAT4, to enhance STAT3-STAT4 signaling and promote Tfh cell differentiation.…”

Section: At B Eg Inning : Tfh Cell S De Velop In the Outer T Cell Zmentioning

confidence: 99%

T follicular helper cell heterogeneity: Time, space, and function

Song

Craft

2019

Immunological Reviews

161

136

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Summary T follicular helper (Tfh) cells play a crucial role in orchestrating the humoral arm of adaptive immune responses. Mature Tfh cells localize to follicles in secondary lymphoid organs (SLOs) where they provide help to B cells in germinal centers (GCs) to facilitate immunoglobulin affinity maturation, class‐switch recombination, and generation of long‐lived plasma cells and memory B cells. Beyond the canonical GC Tfh cells, it has been increasingly appreciated that the Tfh phenotype is highly diverse and dynamic. As naive CD4+ T cells progressively differentiate into Tfh cells, they migrate through a variety of microanatomical locations to obtain signals from other cell types, which in turn alters their phenotypic and functional profiles. We herein review the heterogeneity of Tfh cells marked by the dynamic phenotypic changes accompanying their developmental program. Focusing on the various locations where Tfh and Tfh‐like cells are found, we highlight their diverse states of differentiation. Recognition of Tfh cell heterogeneity has important implications for understanding the nature of T helper cell identity specification, especially the plasticity of the Tfh cells and their ontogeny as related to conventional T helper subsets.

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

Cited by 92 publications

References 79 publications

Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase

Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase

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

T follicular helper cell heterogeneity: Time, space, and function

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