Sirolimus Enhances the Magnitude and Quality of Viral-Specific CD8+ T-Cell Responses to Vaccinia Virus Vaccination in Rhesus Macaques

Turner, Alexandra P.; Shaffer, Virginia; Araki, Koichi; Martens, Christine L.; Turner, P. L.; Gangappa, Shivaprakash; Ford, Mandy L.; Ahmed, Rafi; Kirk, Allan D.; Larsen, Christian

doi:10.1111/j.1600-6143.2010.03407.x

Cited by 95 publications

(85 citation statements)

References 19 publications

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“…It has been reported that attenuation of mTOR signaling promotes memory CD8 + T-cell formation in mice [22,27,28] and in nonhuman primates [29]. However, our results show that activation of mTOR signaling is required for continuous and robust functions of human memory phenotype CD8 + T cells.…”

Section: Discussioncontrasting

confidence: 56%

mTOR signaling promotes a robust and continuous production of IFN‐γ by human memory CD8⁺ T cells and their proliferation

2015

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Human CD8 + T cells are functionally heterogeneous and can be divided into phenotypically and functionally distinct subsets according to CCR7 and CD45RA expression levels. Among these, CCR7 low CD45RA low effector memory CD8 + T cells (Tem) and CCR7 low CD45RA high CD8 + T cells, which are designated as Temra and considered to be terminally differentiated cells, are Ag-experienced T cells but show different functionalities. Here, we show that, while Tem proliferate vigorously and produce IFN-γ persistently and robustly, Temra proliferate poorly and lose the ability to produce IFN-γ over time after TCR stimulation. Temra showed impaired cell growth upon TCR stimulation, which was associated with defective activation of the mammalian target of rapamycin (mTOR) signaling. Furthermore, rapamycin, an inhibitor of mTOR signaling, interfered with the robust and continuous proliferation of and IFN-γ production by Tem at later time points after TCR stimulation. Thus, these data collectively indicate that activation of mTOR signaling is required for the robust functions of Tem cells in humans and suggest that defective mTOR signaling in Temra contributes to their functional impairment.Keywords: CCR7 r CD45RA r CD8 + T cells r IFN-γ r mTOR signaling Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMemory CD8 + T cells develop and persist for a long period of time after the first encounter with exogenous antigen [1,2]. They are phenotypically and functionally heterogeneous and surface markers have been used to delineate different memory T-cell subsets. For example, in mice, CD62L low CD127 low cells are called effector memory cells and CD62L high CD127 high cells are called central memory cells [3,4]. It has been proposed that effector memory cells display a higher ability to produce effector cytokines than central memory cells, whereas the latter display a higher ability to proliferate in response to secondary Ag encounter than the former, and that they are in anatomically different locations [4,5].Correspondence: Dr. Ruka Setoguchi e-mail: ruka@ak.med.kyoto-u.ac.jp Human CD8 + T cells in peripheral blood are also heterogeneous and can be divided into four subpopulations according to their level of surface expression of CCR7 and CD45RA, CCR7 high CD45RA high naïve phenotype, CCR7 high CD45RA low central memory (Tcm) phenotype, CCR7 low CD45RA low effector memory (Tem) phenotype, and CCR7 low CD45RA high CD8 + T cells that are considered to be terminally differentiated cells (Temra) [6,7] The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr kinase that plays an important role in promoting mRNA translation and protein synthesis [16,17]. One of the key players operating downstream of mTOR signaling is ribosomal protein S6 kinase (S6K), and one of its major substrates, ribosomal protein S6 (rpS6), is essential for ribosomal biogenesis [18]. Activation of mTOR signaling in T cells occurs in response to nutrients, cytokines, an...

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Section: Discussioncontrasting

confidence: 56%

mTOR signaling promotes a robust and continuous production of IFN‐γ by human memory CD8⁺ T cells and their proliferation

2015

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“…Therefore, strategies using different combinations, such as chemotherapy and immunotherapy, but also rapamycin and immunotherapy, are being evaluated. Recent studies indeed showed that rapamycin enhances the memory CD8 þ T-cell differentiation and response to viral vaccines in mouse models of chronic infections and tumors (14)(15)(16)27). Therefore, here we analyzed whether rapamycin enhances the effect of our CyaA-E7 vaccine on tumor-specific CD8 þ T-cell responses and tumor eradication in a mouse model of HPV-related tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Araki and colleagues have shown that treatment with rapamycin during acute infection with LCMV enhanced the virus-specific CD8 þ T cells and favored the CD8 þ memory response in mice and macaques (14). Other studies demonstrated the beneficial effect of rapamycin treatment on the vaccine-induced antitumoral response in mice (15) and the vaccine-induced antiviral responses in macaques (16). Human papilloma viruses (HPV) cause proliferative lesions in infected skin and squamous mucosa, resulting in hyperplasias, papillomas, and condylomas.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin Impairs Antitumor CD8+ T-cell Responses and Vaccine-Induced Tumor Eradication

et al. 2015

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The metabolic sensor mTOR broadly regulates cell growth and division in cancer cells, leading to a significant focus on studies of rapamycin and its analogues as candidate anticancer drugs. However, mTOR inhibitors have failed to produce useful clinical efficacy, potentially because mTOR is also critical in T cells implicated in immunosurveillance. Indeed, recent studies using rapamycin have demonstrated the important role of mTOR in differentiation and induction of the CD8 þ memory in T-cell responses associated with antitumor properties.

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“…The positive effects of rapamycin were dissected in nonhuman primates following vaccinia virus vaccination (16). Rapamycin augmented the magnitude, duration, and quality of vaccine-specific T cell responses.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies described that mTOR inhibition by rapamycin treatment during the expansion and contraction phases improved both the quality and quantity of memory T cells after primary immunization in preclinical models (14)(15)(16)(17). Rapamycin seems to prolong the survival of Ag-specific T cells (18,19).…”

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confidence: 99%

Preferential Expansion of Human Virus-Specific Multifunctional Central Memory T Cells by Partial Targeting of the IL-2 Receptor Signaling Pathway: The Key Role of CD4+ T Cells

Schmueck

Fischer

Hammoud

et al. 2012

The Journal of Immunology

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Effector memory T cells are effective in controlling acute infections, but central memory T cells play a key role in long-lasting protection against viruses and tumors. In vivo/in vitro challenge by Ag commonly supports the generation of effector memory T cells with limited longevity. To our knowledge, this study demonstrates for the first time in the human system and under rechallenge conditions that targeting IL-2R by partial mammalian target of rapamycin inhibition or blocking IL-2Rα enriches human CD4+/CD8+ central memory T cells within the virus-specific T cell product associated with enhanced functionality (i.e., multicytokine secretors, including IL-2; enhanced CD137 and CD107a expression on CD8+ and CD4+ T cells, respectively; and killing infected target cells). Remarkably, the effects on CD8+ T cells are mainly mediated via the enhancement of CD4+ T cell function. The data reveal new insights into the role of CD4+ T cell support for the quality of CD8+ T cell memory, even under rechallenge conditions. Moreover, our method offers a new approach to improve the long-lasting efficacy of adoptive T cell therapy in patients.

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Sirolimus Enhances the Magnitude and Quality of Viral-Specific CD8+ T-Cell Responses to Vaccinia Virus Vaccination in Rhesus Macaques

Cited by 95 publications

References 19 publications

mTOR signaling promotes a robust and continuous production of IFN‐γ by human memory CD8⁺ T cells and their proliferation

mTOR signaling promotes a robust and continuous production of IFN‐γ by human memory CD8⁺ T cells and their proliferation

Rapamycin Impairs Antitumor CD8+ T-cell Responses and Vaccine-Induced Tumor Eradication

Preferential Expansion of Human Virus-Specific Multifunctional Central Memory T Cells by Partial Targeting of the IL-2 Receptor Signaling Pathway: The Key Role of CD4+ T Cells

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Sirolimus Enhances the Magnitude and Quality of Viral-Specific CD8+ T-Cell Responses to Vaccinia Virus Vaccination in Rhesus Macaques

Cited by 95 publications

References 19 publications

mTOR signaling promotes a robust and continuous production of IFN‐γ by human memory CD8+ T cells and their proliferation

mTOR signaling promotes a robust and continuous production of IFN‐γ by human memory CD8+ T cells and their proliferation

Rapamycin Impairs Antitumor CD8+ T-cell Responses and Vaccine-Induced Tumor Eradication

Preferential Expansion of Human Virus-Specific Multifunctional Central Memory T Cells by Partial Targeting of the IL-2 Receptor Signaling Pathway: The Key Role of CD4+ T Cells

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mTOR signaling promotes a robust and continuous production of IFN‐γ by human memory CD8⁺ T cells and their proliferation

mTOR signaling promotes a robust and continuous production of IFN‐γ by human memory CD8⁺ T cells and their proliferation