Asynchronous Differentiation of CD8 T Cells That Recognize Dominant and Cryptic Antigens

Baron, Chantal; Meunier, Marie-Christine; Caron, Étienne; Côté, Caroline; Cameron, Mark J.; Kelvin, David J.; LeBlanc, Richard; Rineau, Vincent; Perreault, Claude

doi:10.4049/jimmunol.177.12.8466

Cited by 10 publications

(10 citation statements)

References 85 publications

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“…57 Features having a fold change greater than 1.5 or smaller than À 1.5 and a P-value smaller than 0.05 were considered as significantly regulated based on previous studies using primary T cells. 9,58 Heat maps and hierarchal clustering were done using the MEV (MultiExperiment Viewer) package. 59 The Panther tool (www.pantherdb.org) was used to categorize gene transcripts according to molecular function and biological process (Gene Ontology analysis).…”

Section: Expression Microarray Data Analysismentioning

confidence: 99%

The TGF-β-Smad3 pathway inhibits CD28-dependent cell growth and proliferation of CD4 T cells

et al. 2013

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Transforming growth factor-β (TGF-β) maintains self-tolerance through a constitutive inhibitory effect on T-cell reactivity. In most physiological situations, the tolerogenic effects of TGF-β depend on the canonical signaling molecule Smad3. To characterize how TGF-β/Smad3 signaling contributes to maintenance of T-cell tolerance, we characterized the transcriptional landscape downstream of TGF-β/Smad3 signaling in resting or activated CD4 T cells. We report that in the presence of TGF-β, Smad3 modulates the expression of >400 transcripts. Notably, we identified 40 transcripts whose expression showed Smad3 dependence in both resting and activated cells. This 'signature' confirmed the non-redundant role of Smad3 in TGF-β biology and identified both known and putative immunoregulatory genes. Moreover, we provide genomic and functional evidence that the TGF-β/Smad3 pathway regulates T-cell activation and metabolism. In particular, we show that TGF-β/Smad3 signaling dampens the effect of CD28 stimulation on T-cell growth and proliferation. The impact of TGF-β/Smad3 signals on T-cell activation was similar to that of the mTOR inhibitor Rapamycin. Considering the importance of co-stimulation on the outcome of T-cell activation, we propose that TGF-β-Smad3 signaling may maintain T-cell tolerance by suppressing co-stimulation-dependent mobilization of anabolic pathways.

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Section: Expression Microarray Data Analysismentioning

confidence: 99%

The TGF-β-Smad3 pathway inhibits CD28-dependent cell growth and proliferation of CD4 T cells

et al. 2013

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“…The 1B11 monoclonal antibody recognizes an isoform of CD43 whose expression is induced on activated CD8 and CD4 T cells and correlates with effector function. 23,24 As for Ifngr2 transcripts modulation, discrepancies between IFN-␥RKO and wt hosts were found on day 4 but not day 8 ( Figure 3D). Effector T cells must up-regulate specific integrins to infiltrate nonlymphoid tissues.…”

Section: High Ifn-␥ Exposure and Rapid T-cell Activation In Ifn-␥rko mentioning

confidence: 82%

Graft-versus-host disease causes failure of donor hematopoiesis and lymphopoiesis in interferon-γ receptor-deficient hosts

Delisle

Gaboury

Bélanger

et al. 2008

Blood

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The immunopathologic condition known as graft-versus-host disease (GVHD) results from a type I T-cell process. However, a prototypical type I cytokine, interferon-␥ (IFN-␥), can protect against several manifestations of GVHD in recipients of major histocompatibility complex (MHC)-mismatched hematopoietic cells. We transplanted hematopoietic cells from C3H.SW donors in wild-type (wt) and IFN-␥-receptor-deficient (IFN-␥RKO) MHCmatched C57BL/6 recipients. In IFN-␥RKO recipients, host cells were unresponsive to IFN-␥, whereas wt donor cells were exposed to exceptionally high levels of IFN-␥. From an IFN-␥ perspective, we could therefore evaluate the impact of a loss-of-function on host cells and gain-offunction on donor cells. We found that lack of IFN-␥R prevented up-regulation of MHC proteins on host cells but did not mitigate damage to most target organs. Two salient phenotypes in IFN-␥RKO recipients involved donor cells: lymphoid hypoplasia and hematopoietic failure. Lymphopenia was due to FasL-induced apoptosis and decreased cell proliferation. Bone marrow aplasia resulted from a decreased proliferation of hematopoietic stem/progenitor cells that was associated with down-regulation of 2 genes negatively regulated by IFN-␥: Ccnd1 and Myc. We conclude that IFN-␥ produced by alloreactive T cells may entail a severe graft-versus-graft reaction and could be responsible for cytopenias that are frequently observed in subjects with GVHD. IntroductionInterferon-␥ (IFN-␥) is a master regulator of adaptive immune responses. 1 IFN-␥ modulates hundreds of genes, regulating apoptosis and cell proliferation, antigen processing and presentation, and leukocyte trafficking and effector function. Although our comprehension of the molecular bases of IFN-␥ signaling in the immune system has evolved rapidly, our understanding of how IFN-␥ signals in various cell types are integrated in vivo and impinge on systemic immunopathologic conditions is still rudimentary.GVHD is the most important complication of allogeneic hematopoietic cell transplantation, accounting for most treatmentrelated morbidity and mortality. 2 It is a systemic disease affecting mostly the liver, intestine, skin, and lymphoid organs. [3][4][5] Studies in mouse models of GVHD have reported increased serum levels of IFN-␥ and induction of IFN-␥ transcriptional target genes in the skin and liver. 6,7 However, IFN-␥ was reported to have predominantly a protective influence on GVHD lethality in most though not all studies using IFN-␥-deficient donors, antibody-mediated depletion, or injection of IFN-␥. 4 Use of IFN-␥ receptor 1 chaindeficient (IFN-␥RKO) mice in MHC-mismatched transplants has further shown that the impact of IFN-␥ on GVHD lethality resulted from effects on both donor T cells and host nonhematopoietic cells. 8,9 Thus, alloreactive CD8 T cells from IFN-␥RKO and IFN-␥ deficient donors expand more extensively than CD8 T cells from wt donors. 8 Furthermore, lack of IFN-␥R on host pulmonary parenchyma enhances donor cell migration and expansion within the lu...

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“…Although antibody-based vaccines are protective, they usually are serotype specific. A recent study demonstrated that, utilizing regimens favoring T cell response, it was possible to protect in a mouse-adapted influenza model against homosubtypic and heterosubtypic influenza, as the T cell response generated target conserved epitopes among those strains [83,84]. …”

Section: Immunology Of Npsmentioning

confidence: 99%

Harnessing Nanoparticles for Immunomodulation and Vaccines

2017

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The first successful use of nanoparticles (NPs) for vaccination was reported almost 40 years ago with a virus-like particle-based vaccine against Hepatitis B. Since then, the term NP has been expanded to accommodate a large number of novel nano-sized particles engineered from a range of materials. The great interest in NPs is likely not only a result of the two successful vaccines against hepatitis B and Human Papilloma Virus (HPV) that use this technology, but also due to the versatility of those small-sized particles, as indicated by the wide range of applications reported so far, ranging from medicinal and cosmetics to purely technical applications. In this review, we will focus on the use of NPs, especially virus-like particles (VLPs), in the field of vaccines and will discuss their employment as vaccines, antigen display platforms, adjuvants and drug delivery systems.

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Asynchronous Differentiation of CD8 T Cells That Recognize Dominant and Cryptic Antigens

Cited by 10 publications

References 85 publications

The TGF-β-Smad3 pathway inhibits CD28-dependent cell growth and proliferation of CD4 T cells

The TGF-β-Smad3 pathway inhibits CD28-dependent cell growth and proliferation of CD4 T cells

Graft-versus-host disease causes failure of donor hematopoiesis and lymphopoiesis in interferon-γ receptor-deficient hosts

Harnessing Nanoparticles for Immunomodulation and Vaccines

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