Occurrence of a silencer of the interleukin‐2 gene in naive but not in memory resting T helper lymphocytes

Mouzaki, Αthanasia; Rungger, Duri; Tucci, Alessandra; Doucet, Arlette; Zubler, Rudolf H.

doi:10.1002/eji.1830230711

Cited by 28 publications

(22 citation statements)

References 29 publications

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“…This is supported by studies in the mouse, where memory CD4 T cells have been shown to be in a 'response ready state' and exist in G 1 without being committed to proceed into the S phase of the cell cycle [12]. Their requirements for activation are less stringent than those for naive T cells [13][14][15][16], and the function of memory T cells is to survey for reinvasion after an infection has subsided.…”

Section: Discussionmentioning

confidence: 99%

Memory lymphocytes from tuberculous effusions: purified protein derivative (PPD) stimulates accelerated activation marker expression and cell cycle progression

Lukey

Latouf

Ress

1996

Clinical and Experimental Immunology

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SUMMARYAccelerated PPD-specific proliferation and generation of CD4 cytotoxic effectors by mononuclear leucocytes (MNL) from tuberculous effusions (EMNL) has been previously reported by our laboratory. In order to explore the contribution of the state of activation of MNL to accelerated reactivity, EMNL and peripheral blood (PB)MNL from seven patients with tuberculosis were assessed both ex vivo and after PPD stimulation. Flow cytometry revealed no difference in the activation state (IL-2 receptor and HLA-DR expression) or cell cycle progression ex vivo. However, CD4 CD29 memory T cells were accumulated in EMNL compared with PBMNL. In vitro stimulation of EMNL with PPD resulted in accelerated expression of activation markers and progression through the cell cycle (peak after 4 days), whilst PBMNL exhibited normal activation kinetics (peak after 7 days). Accelerated reactivity could not be accounted for by quantitative differences in effusion CD4 CD29 memory T cells compared with blood, but may be due to a qualitative difference in effusion memory T cells, which are shown to be in a post-activation state of differentiation. T cells entering S and G 2 /M phases of the cell cycle were largely of the activated memory phenotype. Activation marker expression occurred in association with upregulation of CD4 antigen expression on the surface of EMNL. Thus accelerated expression of activation markers and cell cycle progression by CD4 CD29 memory T cells may in part account for accelerated PPD reactivity in tuberculous effusions.

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Section: Discussionmentioning

confidence: 99%

Memory lymphocytes from tuberculous effusions: purified protein derivative (PPD) stimulates accelerated activation marker expression and cell cycle progression

Lukey

Latouf

Ress

1996

Clinical and Experimental Immunology

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“…Since activation studies have demonstrated differences in 11,-2 production by the naive and the memory subpopulation |34), imbalances might be associated with altered expression of DNA-binding proteins. Interestingly, differeniial expression of a silencer of tl:c IL-2 gene has been observed by others [35]. DNA-binding proteins studied by us participate in the induction of IL-2 and several other tymphokine genes [9.10], Therefore, alterations detected by us cannoi be exclusively related to disturbed IL-2 production in patients with rheumatic diseases.…”

Section: Discussionmentioning

confidence: 99%

Analysis of proteins that interact with the IL-2 regulatory region in patients with rheumatic diseases

Becker

Stengl

Stein

et al. 1995

Clinical and Experimental Immunology

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SUMMARY In order to investigate transcriptional regulation of lymphokine genes in rheumatic diseases, peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis (SSc) were analysed for expression of DNA‐binding proteins. Nuclear extracts prepared from unstimulated and mitogen‐activated cells were studied for their ability to bind to 32P‐labelled oligonucleotides containing the AP‐1, NF‐AT, NF‐B and CD28RC sites of the IL‐2 promoter. Using gel mobility‐shift assay, detection of protein binding to the AP‐1 site was reduced in SLE compared with controls. NF‐AT binding activity was enhanced in all groups of patients, and was associated with measures of disease activity in RA. In addition. SSc patients showed increased NF‐×B binding activity. Altered patterns of DNA‐binding proteins suggest disturbed intracellular signalling which may contribute to abnormal lymphokine production in rheumatic diseases.

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“…Our work on the transcriptional regulation of the IL-2 gene in T-cells isolated from mouse splenocytes or human peripheral blood, has presented a more complex mechanism of modulation of IL-2 transcription in primary cells: We showed that a repressor activity exists exclusively in resting naive (CD45RA) but not in memory (CD45RO) CD4 Tcells, that controls the main on-off switch of IL-2 transcription through the NFAT site [60][61][62][63][64][65] This NFATbinding repressor, recently identified as the oncogene product ets-2 [66], is displaced by the active NFAT TF to kick off transcription, and, pertinent to this review, it is stabilized by the calcineurin inhibitors cyclosporin A and FK506 [67].…”

Section: Regulation Of Gene Transcription By Nfatmentioning

confidence: 98%

Immunosuppressive Drugs in HIV Disease

Argyropoulos

Mouzaki²

2006

CTMC

Self Cite

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Hyper activation of the immune system has emerged as an important clinical marker of HIV disease progression to AIDS. During the chronic phase of the disease, chronic immune activation is linked to systemic CD4 T-cell depletion and eventual immune failure. Additionally, the HIV virus per se seems to engage in a form of molecular parasitism for host T-cell signaling pathways and transcription factors (e.g. NFAT). Targeting host T-cell factors that mediate immune activation in conjunction with HAART (Highly Active Antiretroviral Therapy) could be the basis of novel immune-modulatory regimens that avoid the development of mutant viral strains. Hence the three-signal model of T-cell activation provides a framework for the rational selection of immunomodulatory therapies in HIV disease. Within this framework we examine the immunosuppressive, and antiretroviral properties of NFAT (calcineurin) inhibitors (cyclosporine and tacrolimus), the purine rescue pathway inhibitor mycophenolate mofetil and sirolimus (rapamycin). The results of small clinical studies to date are reviewed and they suggest that immunosuppressive medications might be a safe and effective adjunct to HAART in stable HIV disease, when such medications are used in full doses. Finally, we discuss the potential implications of such therapies for solid organ transplantation in HIV patients.

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Occurrence of a silencer of the interleukin‐2 gene in naive but not in memory resting T helper lymphocytes

Cited by 28 publications

References 29 publications

Memory lymphocytes from tuberculous effusions: purified protein derivative (PPD) stimulates accelerated activation marker expression and cell cycle progression

Memory lymphocytes from tuberculous effusions: purified protein derivative (PPD) stimulates accelerated activation marker expression and cell cycle progression

Analysis of proteins that interact with the IL-2 regulatory region in patients with rheumatic diseases

Immunosuppressive Drugs in HIV Disease

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