Lineage-specific differences among CD8+ T cells in their dependence of NF-κB/Rel signaling

Mora, Ana L.; Chen, Daohong; Boothby, Mark; Rubin, Donald H.

doi:10.1002/(sici)1521-4141(199909)29:09<2968::aid-immu2968>3.3.co;2-o

Cited by 10 publications

(15 citation statements)

References 30 publications

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“…Although thymic precursors of the mature T cell subsets were virtually normal in these mice, interference with NF-kB induction led to a substantial reduction of the CD4 + subset and a dramatic decrease of CD8ab + mature T cells in the periphery. 18,19 In addition, our in vitro analyses indicated that IkBa(DN) T cells exhibit increased apoptosis after TCR crosslinking with anti-CD3. 18 These findings suggested that mechanisms operative in the periphery to be responsible for the dramatic deficits in the population of mature T cells because of NF-kB blockade.…”

Section: Introductionmentioning

confidence: 82%

“…Magnetized microbeads for magnetic cell sorting (strepavidin-, anti-CD8, -MHC-II, and -CD62L-conjugated) were obtained from Miltyeni BioTec (Auburn, CA, USA), 7-actinomycin D (7-AAD) from Molecular Probes (Eugene, OR, USA). Most flow cytometry was performed as described previously, 18,19 while Bcl-x L expression was determined by flow cytometry as described 28 and the levels of activated caspase-3 were measured according to the manufacturer's instructions.…”

Section: Antibodies Fluorescence Reagents and Flow Cytometric Analysesmentioning

confidence: 99%

“…18,19 T cells were plated (2.5 Â 10 6 cells/ ml) and cultured overnight at 371C in the presence of plate bound anti-CD3 (10 mg/ml) plus anti-CD28. Total cellular RNA was isolated using TriZol reagent according to the manufacturer's instructions (Life Technologies, Bethesda, MD, USA).…”

Section: Northern Blot Analysesmentioning

confidence: 99%

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Antiapoptotic function of NF-κB in T lymphocytes is influenced by their differentiation status: roles of Fas, c-FLIP, and Bcl-xL

et al. 2003

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Inducible protection from apoptosis in vivo controls the size of cell populations. An important question in this respect is how differentiation affects mechanisms of apoptosis regulation. Among mature T lymphocytes, the NF-jB/Rel transcription factors are coupled to receptors that control cell population sizes by concurrently regulating survival and multiplication. In the present study, we used a transgenic inhibitor of NF-jB/Rel signaling to investigate the role of this pathway in proliferation and death of mature T cells in vivo.The results indicate that NF-jB integrates two critical yet distinct molecular pathways preventing apoptosis affected by the death receptor Fas, coordinately regulating levels of FLIP and Bcl-x L in primary T cells. Surprisingly, NF-jB blockade preferentially impacted naive as compared to memory T cells. The Fas/FasL pathway was linked to these findings by evidence that the abnormalities imposed by NF-jB inhibition were ameliorated by Fas deficiency, particularly for the CD4 + lineage. Moreover, levels of an inhibitor of Fas-mediated apoptosis, c-FLIP, were diminished in cells expressing the transgenic inhibitor. NF-jB was also linked to T cell survival in vivo by mediating induction of Bcl-x L : restoration of Bcl-x L levels reversed the preferential deficit of naive T cells, differentially impacting the CD4 and CD8 subsets. These results show that promoting survival and effective multiplication are central roles for NF-jB in T lymphoid homeostasis in vivo, but this effect and its underlying mechanisms are influenced by the developmental state of the lymphocyte.

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Section: Introductionmentioning

confidence: 82%

Section: Antibodies Fluorescence Reagents and Flow Cytometric Analysesmentioning

confidence: 99%

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Antiapoptotic function of NF-κB in T lymphocytes is influenced by their differentiation status: roles of Fas, c-FLIP, and Bcl-xL

et al. 2003

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“…Single-cell suspensions were prepared from spleen and lymph nodes as described previously (41). Retrovirus-containing supernatants were collected 48 h after transfection of the ⌽NX ecotropic packaging cell line with retrovector plasmids and centrifuged (1 h, 10,000 ϫ g) with peptide-activated splenocytes from IL-4R␣ Ϫ/Ϫ DO11.10-TCR-transgenic mice as described elsewhere (37,42).…”

Section: Retroviral Transduction and Th2 Polarizationmentioning

confidence: 99%

New Programming of IL-4 Receptor Signal Transduction in Activated T Cells: Stat6 Induction and Th2 Differentiation Mediated by IL-4Rα Lacking Cytoplasmic Tyrosines

Mora

Stephenson

Enerson

et al. 2003

The Journal of Immunology

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Signaling by the IL-4 receptor α-chain (IL-4Rα) is a key determinant of the development of the Th2 lineage of effector T cells. Studies performed in tissue culture cell lines have indicated that tyrosines of the IL-4Rα cytoplasmic tail are necessary for the induction of Stat6, a transcription factor required for Th2 differentiation. Surprisingly, we have found that in activated T cells, IL-4Rα chains lacking all cytoplasmic tyrosines promote induction of this IL-4-specific transcription factor and efficient commitment to the Th2 lineage. Mutagenesis of a tyrosine-free cytoplasmic tail identifies a requirement for the serine-rich ID-1 region in this new program of IL-4R signal transduction observed in activated T cells. Additional findings suggest that an extracellular signal-regulated kinase pathway can be necessary and sufficient for the ability of such tyrosine-free IL-4Rα chains to mediate Stat6 induction. These results provide novel evidence that the molecular mechanisms by which a cytokine specifically induces a Stat transcription factor can depend on the activation state of T lymphoid cells. Furthermore, the data suggest that one pathway by which such new programming may be achieved is mediated by extracellular signal-regulated mitogen-activated protein kinases.

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“…Thus, the I B␣(⌬N)-Tg mice provide an experimental system to define the role of NF-B in protective CD4 ϩ T cell responses to T. gondii. To date, these mice have not been widely used to study the role of NF-B in T cell responses to infection with only a single study which demonstrated that CD8 ϩ intraepithelial lymphocyte cytotoxicity during enteric reovirus infection is reduced in I B␣(⌬N)-Tg mice (43). The studies presented here reveal that although the I B␣(⌬N)-Tg CD4 ϩ T cells become activated in response to infection, they have a major defect in their ability to proliferate and produce IFN-␥ following stimulation with parasite Ags.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of NF-κB Activity in T and NK Cells Results in Defective Effector Cell Expansion and Production of IFN-γ Required for Resistance to Toxoplasma gondii

Tato

Villarino

Caamaño

et al. 2003

The Journal of Immunology

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To define the role of NF-κB in the development of T cell responses required for resistance to Toxoplasma gondii, mice in which T cells are transgenic for a degradation-resistant (ΔN) form of IκBα, an inhibitor of NF-κB, were challenged with T. gondii and their response to infection compared with control mice. IκBα(ΔN)-transgenic (Tg) mice succumbed to T. gondii infection between days 12 and 35, and death was associated with an increased parasite burden compared with wild-type (Wt) controls. Analysis of the responses of infected mice revealed that IL-12 responses were comparable between strains, but Tg mice had a marked reduction in systemic levels of IFN-γ, the major mediator of resistance to T. gondii. In addition, the infection-induced increase in NK cell activity observed in Wt mice was absent from Tg mice and this correlated with NK cell expression of the transgene. Infection-induced activation of CD4+ T cells was similar in Wt and Tg mice, but expansion of activated CD4+T cells was markedly reduced in the Tg mice. This difference in T cell numbers correlated with a reduced capacity of these cells to proliferate after stimulation and was associated with a major defect in the ability of CD4+ T cells from infected mice to produce IFN-γ. Together, these studies reveal that inhibition of NF-κB activity in T and NK cells results in defective effector cell expansion and production of IFN-γ required for resistance to T. gondii.

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Lineage-specific differences among CD8+ T cells in their dependence of NF-κB/Rel signaling

Cited by 10 publications

References 30 publications

Antiapoptotic function of NF-κB in T lymphocytes is influenced by their differentiation status: roles of Fas, c-FLIP, and Bcl-xL

Antiapoptotic function of NF-κB in T lymphocytes is influenced by their differentiation status: roles of Fas, c-FLIP, and Bcl-xL

New Programming of IL-4 Receptor Signal Transduction in Activated T Cells: Stat6 Induction and Th2 Differentiation Mediated by IL-4Rα Lacking Cytoplasmic Tyrosines

Inhibition of NF-κB Activity in T and NK Cells Results in Defective Effector Cell Expansion and Production of IFN-γ Required for Resistance to Toxoplasma gondii

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