Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of human CD3-positive T cells from SLE and controls reveals activation of mTOR controls the loss of TCRI? in lupus T cells through HRES-1/Rab4-regulated lysosomal degradation


ABSTRACT: CD3-positive T cells were negatively isolated from 10 SLE patients and 9 healthy controls without SLE. All of the SLE samples and control samples were compared with one another to identify baseline differences in expression due to the disease. Next, T cell preparations from 4 of the control subjects were stimulated with either Nitric Oxide (NOC-18) 600 uM for 24hr or stimulated through CD3/CD28 for 24hr to determine which genes were responsive to these signaling mechanisms. Here, we show that activity of the mammalian target of rapamycin (mTOR), which is a sensor of the mitochondrial transmembrane potential, is increased in SLE T cells. Activation of mTOR was inducible by NO, a key trigger of MHP which in turn enhanced the expression of HRES-1/Rab4, a small GTPase that regulates recycling of surface receptors through early endosomes. Expression of HRES-1/Rab4 was increased in SLE T cells and, in accordance with its dominant impact on the endocytic recycling of CD4, it was inversely correlated with diminished CD4 expression. HRES-1/Rab4 over-expression was also inversely correlated with diminished TCRζ protein levels. Combined with follow up studies, these results suggest that activation of mTOR causes the loss of TCRζ in lupus T cells through HRES-1/Rab4-dependent lysosomal degradation. Experiment Overall Design: 10 replicate T cell samples from SLE (Lupus) patients Experiment Overall Design: 9 replicate T cell samples from healthy control (BC) subjects Experiment Overall Design: 4 replicate Nitric Oxide (NOC-18) stimulated T cell samples from 4 of the control subjects Experiment Overall Design: 4 replicate CD3/CD28 stimulated T cell samples from 4 of the control subjects

ORGANISM(S): Homo sapiens

SUBMITTER: Frank Middleton 

PROVIDER: E-GEOD-13887 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Activation of mammalian target of rapamycin controls the loss of TCRzeta in lupus T cells through HRES-1/Rab4-regulated lysosomal degradation.

Fernandez David R DR   Telarico Tiffany T   Bonilla Eduardo E   Li Qing Q   Banerjee Sanjay S   Middleton Frank A FA   Phillips Paul E PE   Crow Mary K MK   Oess Stefanie S   Muller-Esterl Werner W   Perl Andras A  

Journal of immunology (Baltimore, Md. : 1950) 20090201 4


Persistent mitochondrial hyperpolarization (MHP) and enhanced calcium fluxing underlie aberrant T cell activation and death pathway selection in systemic lupus erythematosus. Treatment with rapamycin, which effectively controls disease activity, normalizes CD3/CD28-induced calcium fluxing but fails to influence MHP, suggesting that altered calcium fluxing is downstream or independent of mitochondrial dysfunction. In this article, we show that activity of the mammalian target of rapamycin (mTOR),  ...[more]

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