Augmentation in Expression of Activation-Induced Genes Differentiates Memory from Naive CD4+ T Cells and Is a Molecular Mechanism for Enhanced Cellular Response of Memory CD4+ T Cells

Liu, Kebin; Liu, Yu; Prabhu, Vinayakumar; Young, Lynn; Becker, Kevin G.; Munson, Peter J.; Weng, Nan‐ping

doi:10.4049/jimmunol.166.12.7335

Cited by 59 publications

(51 citation statements)

References 67 publications

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“…1. PBMC from all these individuals (total n ϭ 40) were cultured in the presence or absence of optimal stimulatory levels of HDM for 12, 24, and 48 h. These time points were selected because they bracket the period during which expression of T cell activation markers is maximal following in vitro stimulation (49). Total RNA was extracted from PBMC at the termination of these cultures.…”

Section: Study Design and Statistical Analysesmentioning

confidence: 99%

Identification of Novel Th2-Associated Genes in T Memory Responses to Allergens

Bosco

McKenna

Devitt

et al. 2006

The Journal of Immunology

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Atopic diseases are associated with hyperexpression of Th2 cytokines by allergen-specific T memory cells. However, clinical trials with recently developed Th2 inhibitors in atopics have proven disappointing, suggesting underlying complexities in atopy pathogenesis which are not satisfactorily explained via the classical Th1/Th2 paradigm. One likely possibility is that additional Th2-associated genes which are central to disease pathogenesis remain unidentified. The aim of the present study was to identify such novel Th2-associated genes in recall responses to the inhalant allergen house dust mite. In contrast to earlier human microarray studies in atopy which focused on mitogen-activated T cell lines and clones, we concentrated on PBMC-derived primary T cells stimulated under more physiological conditions of low dose allergen exposure. We screened initially for allergen-induced gene activation by microarray, and validated novel genes in independent panels of subjects by quantitative RT-PCR. Kinetic analysis of allergen responses in PBMC revealed an early wave of novel atopy-associated genes involved in signaling which were coexpressed with IL-4 and IL-4R, followed by a later wave of genes encoding the classical Th2 effector cytokines. We further demonstrate that these novel activation-associated Th2 genes up-regulate in response to another atopy-associated physiological stimulus bacterial superantigen, but remain quiescent in nonphysiological responses in primary T cells or cell lines driven by potent mitogens, which may account for their failure to be detected in earlier microarray studies.

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Section: Study Design and Statistical Analysesmentioning

confidence: 99%

Identification of Novel Th2-Associated Genes in T Memory Responses to Allergens

Bosco

McKenna

Devitt

et al. 2006

The Journal of Immunology

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“…Isolation of primary human CD4 þ T cells from peripheral blood and stimulation in vitro Human primary CD4 þ T cells were isolated from donor peripheral blood by negative immunomagnetic separation as previously reported (Weng et al, 1995;Liu et al, 2001). For stimulation, cells were resuspended in RPMI 1640 medium supplemented with 10% FBS at a concentration of 2-5 Â 10 6 cells/ml, then mixed with mAbs to CD3 and CD28 immobilized on Dynal beads (Lake Success, NY, USA) at a 1 : 1 cell : bead ratio and were incubated for the indicated time points prior to harvest.…”

Section: Real-time Rt-pcrmentioning

confidence: 99%

Modulation of specific protein expression levels by PTEN: identification of AKAP121, DHFR, G3BP, Rap1 and RCC1 as potential targets of PTEN

et al. 2005

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The tumor suppressor PTEN is mutated in a high percentage of human cancers, and is implicated in pathways regulating cell growth, proliferation, survival, and migration. Despite significant advances, our understanding of its mechanisms of action remains incomplete. We have used a high-throughput proteomic immunoblotting approach to identify proteins whose expression levels are modulated by PTEN. Out of over 800 proteins screened, 22 proteins showed significant changes in expression. Five proteins that exhibited two-fold or greater changes in expression level were further characterized. AKAP121 and G3BP expression was reduced, while dihydrofolate reductase (DHFR), Rap1 and RCC1 expression was elevated in response to PTEN expression in a PTEN-null T-cell leukemia line. The phosphatase activity of PTEN was required for these effects. However, direct inhibition of PI-3 Kinase could mimic PTEN in modulating expression of DHFR, G3BP, Rap1 and RCC1, but not AKAP121. Real-time PCR showed that the effects of PTEN were primarily post-transcriptional, and would not have been revealed by mRNA-based screens. We conclude from these data that PTEN can modulate the expression level of a number of different proteins. The identified proteins have the potential to serve as previously unrecognized effectors of PTEN, and suggest the existence of additional complexity in the modes by which PTEN can regulate cellular biology.

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“…Activation of these cells via their cognate antigen receptor is the predominant feature of an efficient immune response. On activation, expression of numerous surface markers is modulated, 17,18 cytokines are secreted, and cells can undergo as many as 6 to 8 divisions. Here, we have assessed whether expression of the HTLV receptor on T lymphocytes is modulated by their activation state.…”

Section: Introductionmentioning

confidence: 99%

The HTLV receptor is an early T-cell activation marker whose expression requires de novo protein synthesis

Manel

Kinet

Battini

et al. 2003

Blood

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The human T-cell leukemia virus type 1 (HTLV) is the first isolated human retrovirus, but its receptor has yet to be identified, in part due to its ubiquitous expression. Here we report that quiescent CD4 and CD8 T lymphocytes do not express this receptor, as monitored with a soluble receptor-binding domain derived from the HTLV envelope. However, HTLV receptor is an early activation marker in neonatal and adult T lymphocytes, detected as early as 4 hours following T-cell-receptor (TCR) stimulation. This induced surface expression of the HTLV receptor requires de novo protein synthesis and results in a wide distribution on the surface of activated lymphocytes. Moreover, the distribution of the HTLV receptor is independent of TCR/CD3-capped membrane structures, as observed by confocal immunofluorescence microscopy. To determine whether HTLV receptor up-regulation specifically requires TCR-mediated signals or, alternatively, is dependent on more generalized cell cycle entry/proliferation signals, its expression was monitored in interleukin 7 (IL-7)-stimulated neonatal and adult T cells.Neonatal, but not adult, lymphocytes proliferate in response to IL-7 and HTLV receptor expression is restricted to the former population. Thus, HTLV receptor expression appears to be an early marker of cell cycle entry. Up IntroductionThe human T-cell leukemia virus type 1 (HTLV-1), the first characterized human retrovirus, 1 is present in all areas of the world as either an endemic or a sporadic infectious agent. 2 In endemic areas, HTLV-1 transmission seems to occur mostly from mother to infant through breast-feeding. 3 The exceptionally broad tropism of HTLV-1 in vitro 4,5 contrasts with the finding that in vivo, HTLV-1 is found primarily in CD4 ϩ lymphocytes and less frequently in other mononuclear blood cells. 6,7 Studies of this apparent discrepancy have been hindered by the high cytotoxicity of HTLV envelopes and their dependence on cell-to-cell contact for infection and spreading. 4,8,9 Moreover, investigations have been limited because the HTLV envelope receptor remains unidentified, even though multiple cell surface components including adhesion molecules, 10,11 matrix-associated proteins, 12 lipids, 13 and lipid rafts, 14 have been implicated in HTLV envelope (Env)-mediated membrane fusion and virus transmission.The HTLV-1 Env receptor-binding determinants are entirely contained within the extracellular surface component (SU). 4,15 Recently, we demonstrated that the amino-terminal 215 amino acids of the SU harbors the receptor-binding domain (RBD) of HTLV Env. 16 The binding specificity of a soluble tagged construct encompassing this region (H RBD ) has been demonstrated by its efficient competition with HTLV Env-mediated cell fusion and infection (F.J.K., E. N. Garrido, N.M., M.S., J.-L.B., manuscript in preparation).Using the RBD of HTLV Env, we have now tracked HTLV receptor expression on T lymphocytes, which have been reported to be a major HTLV-1 reservoir in vivo. Circulating T lymphocytes are almost entirely in th...

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Augmentation in Expression of Activation-Induced Genes Differentiates Memory from Naive CD4+ T Cells and Is a Molecular Mechanism for Enhanced Cellular Response of Memory CD4+ T Cells

Cited by 59 publications

References 67 publications

Identification of Novel Th2-Associated Genes in T Memory Responses to Allergens

Identification of Novel Th2-Associated Genes in T Memory Responses to Allergens

Modulation of specific protein expression levels by PTEN: identification of AKAP121, DHFR, G3BP, Rap1 and RCC1 as potential targets of PTEN

The HTLV receptor is an early T-cell activation marker whose expression requires de novo protein synthesis

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