Membrane and transmembrane signaling in Herpesvirus saimiri-transformed human CD4+ and CD8+ T lymphocytes is ATM-independent.

Rivero-Carmena, Miguel; Porras, Óscar; Peláez, Blondineth; Pacheco‐Castro, Alberto; Gatti, Richard A.; Regueiro, José R.

doi:10.1093/intimm/12.6.927

Cited by 16 publications

(11 citation statements)

References 38 publications

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“…A recent study by Rivero‐Carmena et al. [38] showed that HVS‐transformed mature peripheral T lymphocytes from AT patients do not exhibit any activation deficit and that the cells do not have an intrinsic immune functional defect. Although they demonstrated that these transformed T cells retained important features of AT cells (i.e.…”

Section: Discussionmentioning

confidence: 99%

Deficiencies in CD4+ and CD8+ T cell subsets in ataxia telangiectasia

Schubert

Reichenbach

Zielen

2002

Clinical and Experimental Immunology

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SUMMARY Chronic sinopulmonary infections that are associated with immunodeficiency are one of the leading causes of death in the multi‐systemic disease ataxia telangiectasia (AT). Immunological investigations of AT patients revealed a broad spectrum of defects in the humoral and the cellular immune system. Based on their important role in host defence the aim of our study was an extensive analysis of cell distribution and function of CD4+ and CD8+ T lymphocytes and NK cells. We found that naive (CD45RA+) CD4+ lymphocytes, as well as CD8+/CD45RA+ lymphocytes, are decreased, whereas NK cells (CD3−/CD16+CD56+) are significantly elevated in AT patients. In our culture system proliferation and cytokine production was normal in purified memory (CD45RO+) lymphocytes after stimulation with phorbol‐12,13‐dibutyrate (PBu2) and after PHA activation, indicating that differences in proliferation and cytokine production are due solely to reduced numbers of CD45RA+ lymphocytes. However, activation, and especially intracellular interferon production of AT lymphocytes, seem to follow different kinetics compared to controls. In contrast to polyclonal activation, stimulation via the T cell receptor results consistently in a reduced immune response. Taken together, our results suggest that deficiency of immunocompetent cells and an intrinsic immune activation defect are responsible for the immunodeficiency in AT.

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Section: Discussionmentioning

confidence: 99%

Deficiencies in CD4+ and CD8+ T cell subsets in ataxia telangiectasia

Schubert

Reichenbach

Zielen

2002

Clinical and Experimental Immunology

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“…For RNA interference, we used published siRNAs specific for ATM [32], NBS1 (hNBS1.1 CAGGAGGAAGATGTCAATG dTdT or hNBS1.2 GGCGUGUCAGUUGAUGAAA dTdT), MKK3 (hMEKK3-258 GCACGGUCGACUGUUUCUA dTdT), p38MAPK (Dharmacon RNATtechnology) that were transfected into cells with Oligofectamine (Invitrogen). Herpesvirus saimiri-immortalized CD4 + T cells from a patient with A-T (ATM mutation 5908 C>T) and from a control donor [53], as well as spontaneously immortalized T cells from NBS patient (NBS mutation 657de15) and for a control donor were cultured as described [54].…”

Section: Methodsmentioning

confidence: 99%

Critical Involvement of the ATM-Dependent DNA Damage Response in the Apoptotic Demise of HIV-1-Elicited Syncytia

et al. 2008

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DNA damage can activate the oncosuppressor protein ataxia telangiectasia mutated (ATM), which phosphorylates the histone H2AX within characteristic DNA damage foci. Here, we show that ATM undergoes an activating phosphorylation in syncytia elicited by the envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) in vitro. This was accompanied by aggregation of ATM in discrete nuclear foci that also contained phospho-histone H2AX. DNA damage foci containing phosphorylated ATM and H2AX were detectable in syncytia present in the brain or lymph nodes from patients with HIV-1 infection, as well as in a fraction of blood leukocytes, correlating with viral status. Knockdown of ATM or of its obligate activating factor NBS1 (Nijmegen breakage syndrome 1 protein), as well as pharmacological inhibition of ATM with KU-55933, inhibited H2AX phosphorylation and prevented Env-elicited syncytia from undergoing apoptosis. ATM was found indispensable for the activation of MAP kinase p38, which catalyzes the activating phosphorylation of p53 on serine 46, thereby causing p53 dependent apoptosis. Both wild type HIV-1 and an HIV-1 mutant lacking integrase activity induced syncytial apoptosis, which could be suppressed by inhibiting ATM. HIV-1-infected T lymphoblasts from patients with inactivating ATM or NBS1 mutations also exhibited reduced syncytial apoptosis. Altogether these results indicate that apoptosis induced by a fusogenic HIV-1 Env follows a pro-apoptotic pathway involving the sequential activation of ATM, p38MAPK and p53.

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“…After two washes with PBS buffer, the cells were analyzed in an Epics Elite Analyzer cytofluorometer (Coulter, Hialeah, FL). Isotype-matched, irrelevant antibodies were used to define background fluorescence [15]. Data were collected on 10 4 viable cells as determined by electronic gating from a tight region around the lymphocyte population on the forward-scatter/side-scatter parameters dot-plot.…”

Section: Phenotypical Analysesmentioning

confidence: 99%

“…It has been shown [13][14][15][16][17][18][19][20][21][22] that transformed T cells from congenital ID preserve the original defects. We therefore reasoned that transformed T cells from CHS patients might be useful as a tool to study the role of CHS1/LYST in cytolytic lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

Herpesvirus saimiri-transformed CD8+ T cells as a tool to study Chediak-Higashi syndrome cytolytic lymphocytes

Martín-Fernández

Cabanillas

Rivero-Carmena

et al. 2005

Journal of Leukocyte Biology

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Cytolytic CD8+ T lymphocytes are the main cell type involved in the fatal lymphoproliferative-accelerated phase of the Chediak-Higashi syndrome (CHS). To generate a cellular tool to study the defects of this T cell subset in vitro, we have used Herpesvirus saimiri, a lymphotropic virus that transforms human T lymphocytes into extended growth and in addition, endows them with natural killer (NK) features. Transformed CHS CD8+ T cells were generated and characterized in comparison with healthy controls. The results showed that transformed CHS T cells maintained the defects described in primary CHS lymphocytes, such as giant secretory lysosomes and impaired NK and T cell receptor/CD3-induced, perforin-mediated cytolytic activity [which, however, could be restored after extended culture in the presence of interleukin-2 (IL-2)]. Upon activation with phorbol ester plus calcium ionophore or upon extended culture with IL-2, transformed CHS T cells showed normal, perforin-independent plasma membrane CD178/CD95L/FasL-mediated cytolytic activity but negligible secretion of microvesicle-bound CD95L. Transformed (and primary) CHS T cells were otherwise normal for cytolysis-independent activation functions, such as proliferation, surface expression of several activation markers including major histocompatibility complex class II, and cytokine or surface activation-marker induction. Therefore, the CHS protein [CHS1/LYST (for lysosomal traffic regulator)] can be dispensable for certain NK and T cell cytolytic activities of activated CHS CD8+ T lymphocytes, but it seems to be required for microvesicle secretion of CD95L. We conclude that transformed CHS T cells may be useful as a tool to study in vitro the relative role of CHS1/LYST in NK and T lymphocyte cytolysis and antigen presentation.

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Membrane and transmembrane signaling in Herpesvirus saimiri-transformed human CD4+ and CD8+ T lymphocytes is ATM-independent.

Cited by 16 publications

References 38 publications

Deficiencies in CD4+ and CD8+ T cell subsets in ataxia telangiectasia

Deficiencies in CD4+ and CD8+ T cell subsets in ataxia telangiectasia

Critical Involvement of the ATM-Dependent DNA Damage Response in the Apoptotic Demise of HIV-1-Elicited Syncytia

Herpesvirus saimiri-transformed CD8+ T cells as a tool to study Chediak-Higashi syndrome cytolytic lymphocytes

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