Transcriptome profiling of CTLs regulated by rapamycin using RNA-Seq

Mattson, Elliot; Xu, Lingyang; Li, Lei; Liu, George E.; Xiao, Zhengguo

doi:10.1007/s00251-014-0790-5

Cited by 9 publications

(8 citation statements)

References 50 publications

(81 reference statements)

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“…Memory formation is the gold standard for vaccination, IL-12 is required for memory CTL formation, and IL-12 signaling can be regulated by other regulators, such as rapamycin 30 , 44 , 45 . To test the involvement of exosomes in this IL-12-driven memory programing, GW4869, an nSMase2 inhibitor 27 , 46 – 50 used largely in vitro rather than in vivo 51 , was added in the presence of IL-12 stimulation for naïve CD8 + T cells 22 .…”

Section: Resultsmentioning

confidence: 99%

IL-12 stimulates CTLs to secrete exosomes capable of activating bystander CD8+ T cells

Jay

Wang

et al. 2017

Sci Rep

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An effective cytotoxic T lymphocyte (CTL) response against intracellular pathogens is generally accomplished by immense CTL expansion and activation, which can destroy infected cells. Vigorous immune responses can lead to activation of bystander CD8+ T cells, but the contribution from antigen-specific CTLs is not well understood. We found that CTLs secrete extracellular vesicles following antigen stimulation. These CTL-derived vesicles contain CTL proteins and exhibit markers and size profiles consistent with exosomes. Interestingly, further stimulation of CTLs with IL-12 impacts exosome size and leads to selective enrichment of certain exosomal proteins. More important, exosomes from IL-12-stimulated CTLs directly activated bystander naïve CD8+ T cells to produce interferon-γ (IFNγ) and granzyme B (GZB) in the absence of antigens, whereas control exosomes derived from antigen-stimulated CTLs did not. In addition, IL-12 induced exosomes are able to strengthen the effects of weak antigen stimulation on CTLs. Proteomic analysis demonstrates that IL-12 stimulation alters catalytic and binding activities of proteins in CTL exosomes. Our findings indicate that the biological function and morphology of exosomes secreted by CTLs can be influenced by the type of stimulation CTLs receive. Thus, a fully functional, ongoing, antigen-specific CTL response may influence bystander CD8+ T cells through secretion of exosomes.

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Section: Resultsmentioning

confidence: 99%

IL-12 stimulates CTLs to secrete exosomes capable of activating bystander CD8+ T cells

Jay

Wang

et al. 2017

Sci Rep

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“…In CD8 + T-cells, mTORC1 controls, for example, glucose uptake and glycolysis during activation and effector phases and also participates in the signaling generated by the antigen recognition receptor (TCR) and cytokines ( Jacobs et al., 2008 ; Buck et al., 2015 ; Chang and Pearce, 2016 ). Even though rapamycin has been commonly used in organ transplantation to prevent graft rejection ( Augustine et al., 2007 ), several studies have reported that mTOR inhibition by treatment with low and continuous doses of rapamycin during the immune challenge of CD8 + T cells could improve the function and memory formation following viral infections or tumor challenges ( Araki et al., 2009 ; Rao et al., 2010 ; Li et al., 2011 ; Turner et al., 2011 ; Bassett et al., 2012 ; Mattson et al., 2014 ; Shrestha et al., 2014 ).…”

Section: Introductionmentioning

confidence: 99%

“…The transcriptome of activated CD8 + T cells treated with rapamycin revealed that most genes modulated by mTOR inhibitor are associated with apoptosis, survival, maintenance, and cell migration, which take part in the CD8 + T cell programming after activation ( Mattson et al., 2014 ; Borsa et al., 2019 ). Moreover, a clinical trial found that elderly people immunized against influenza and treated with rapamycin had a response 20% higher in antibody titer than the placebo group, paralleled by increased T cells life span, improving immune function and reducing infections ( Mannick et al., 2014 ; Mannick et al., 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Rapamycin Improves the Response of Effector and Memory CD8+ T Cells Induced by Immunization With ASP2 of Trypanosoma cruzi

Moraschi

Noronha

Ferreira

et al. 2021

Front. Cell. Infect. Microbiol.

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Deficiency in memory formation and increased immunosenescence are pivotal features of Trypanosoma cruzi infection proposed to play a role in parasite persistence and disease development. The vaccination protocol that consists in a prime with plasmid DNA followed by the boost with a deficient recombinant human adenovirus type 5, both carrying the ASP2 gene of T. cruzi, is a powerful strategy to elicit effector memory CD8+ T-cells against this parasite. In virus infections, the inhibition of mTOR, a kinase involved in several biological processes, improves the response of memory CD8+ T-cells. Therefore, our aim was to assess the role of rapamycin, the pharmacological inhibitor of mTOR, in CD8+ T response against T. cruzi induced by heterologous prime-boost vaccine. For this purpose, C57BL/6 or A/Sn mice were immunized and daily treated with rapamycin for 34 days. CD8+ T-cells response was evaluated by immunophenotyping, intracellular staining, ELISpot assay and in vivo cytotoxicity. In comparison with vehicle-injection, rapamycin administration during immunization enhanced the frequency of ASP2-specific CD8+ T-cells and the percentage of the polyfunctional population, which degranulated (CD107a+) and secreted both interferon gamma (IFNγ) and tumor necrosis factor (TNF). The beneficial effects were long-lasting and could be detected 95 days after priming. Moreover, the effects were detected in mice immunized with ten-fold lower doses of plasmid/adenovirus. Additionally, the highly susceptible to T. cruzi infection A/Sn mice, when immunized with low vaccine doses, treated with rapamycin, and challenged with trypomastigote forms of the Y strain showed a survival rate of 100%, compared with 42% in vehicle-injected group. Trying to shed light on the biological mechanisms involved in these beneficial effects on CD8+ T-cells by mTOR inhibition after immunization, we showed that in vivo proliferation was higher after rapamycin treatment compared with vehicle-injected group. Taken together, our data provide a new approach to vaccine development against intracellular parasites, placing the mTOR inhibitor rapamycin as an adjuvant to improve effective CD8+ T-cell response.

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“…Using 1.5-fold as the cutoff, 467 proteins were enhanced (or unique) in D1E (Supplementary Table 2), and 233 in D3E (Supplementary Table 3). We next explored how these skewed (differential) protein profiles were associated with downstream effector function using Ingenuity Pathway Analysis (IPA) (73). The two different profiles were predicted to relate to similar biological functions, such as enhancing the activation, movement of cells, inhibiting apoptosis, and cell death (Table 1).…”

Section: Resultsmentioning

confidence: 99%

CTL-Derived Exosomes Enhance the Activation of CTLs Stimulated by Low-Affinity Peptides

Wang

et al. 2019

Front. Immunol.

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Cytotoxic T cells (CTLs) bind to peptides presented by MHC I (pMHC) through T cell receptors of various affinities. Low-affinity CTLs are important for the control of intracellular pathogens and cancers; however, the mechanisms by which these lower affinity CTLs are activated and maintained are not well understood. We recently discovered that fully activated CTLs stimulated by strong-affinity peptides in the presence of IL-12 are able to secrete exosomes that, in turn, stimulate bystander CTLs without requiring the presence of antigen. We hypothesized that exosomes secreted by high-affinity CTLs could strengthen the activation of low-affinity CTLs. Naive OT-I CD8+ cells were stimulated with altered N4 peptides of different affinities in the presence or absence of Exo. The presence of Exo preferentially increased cell proliferation and enhanced the production of IFNγ in CTLs stimulated by low-affinity peptides. The expression of granzyme B (GZB) was augmented in all affinities, with higher GZB production in low-affinity stimulated CTLs than in high-affinity stimulated ones. Exosomes promoted the rapid activation of low-affinity CTLs, which remained responsive to exosomes for a prolonged duration. Unexpectedly, exosomes could be induced quickly (24 h) following CTL activation and at a higher quantity per cell than later (72 h). While exosome protein profiles vary significantly between early exosomes and their later-derived counterparts, both appear to have similar downstream functions. These results reveal a potential mechanism for fully activated CTLs in activating lower-affinity CTLs that may have important implications in boosting the function of low-affinity CTLs in immunotherapy for cancers and chronic viral infections.

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Transcriptome profiling of CTLs regulated by rapamycin using RNA-Seq

Cited by 9 publications

References 50 publications

IL-12 stimulates CTLs to secrete exosomes capable of activating bystander CD8+ T cells

IL-12 stimulates CTLs to secrete exosomes capable of activating bystander CD8+ T cells

Rapamycin Improves the Response of Effector and Memory CD8+ T Cells Induced by Immunization With ASP2 of Trypanosoma cruzi

CTL-Derived Exosomes Enhance the Activation of CTLs Stimulated by Low-Affinity Peptides

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