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Human CD4+ memory T cells are preferential targets for bystander activation and apoptosis

ABSTRACT: There is much evidence that T cells may be activated via mechanisms which act independently of direct TCR ligation. Despite this, the question of whether such forms of ‘bystander’ T cell activation occur during immune responses is hotly debated. To address some outstanding questions, we set up an in vitro system within which to analyse bystander T cell activation in human T cells, in the absence of the possibility for TCR cross-reactivity. In addition, we have investigated the genetic, phenotypic, and functional characteristics of bystander activated T cells. Here, we show that bystander T cell activation is, indeed, observed during a specific immune response, and that it occurs preferentially amongst CD4+ memory T cells. Furthermore, bystander activated T cells display a distinct gene expression profile. The mechanism for bystander T cell activation involves soluble factors, and the outcome is an elevated level of apoptosis. This may provide an explanation for the attrition of T cell memory pools of heterologous specificity during immune responses to pathogens such as viruses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE13738 | GEO | 2009/02/11

SECONDARY ACCESSION(S): PRJNA109385

REPOSITORIES: GEO

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Project description:Background: The radiation bystander response is an important component of the overall response of cells to radiation and critical to understanding health risks of radiation exposure to humans. The mechanism of radiation response includes inter-cellular signaling and intra-cellular communication by which the bystander signal is propagated. Methods: We measured the bystander response to 1Gy a-particle radiation in Mrad9-/- mouse stem cells and H1299shRAD9 cells, using chromosomal aberration and micronucleus formation as DNA damage endpoints. In the H1299 model we used whole genome microarray analyses to profile the transcriptome of irradiated and bystander cells. Results: We investigated the role of RAD9 in the bystander response and showed that depletion or mutation of RAD9 had an effect of increasing chromosomal structural damage as well as micronucleus formation in bystander cells. The enhancement of the damage effect correlated strongly with a transcriptomic response in critical pathways. RAD9 depletion affected many pathways in the cell, including the UV-MAPK pathway, involving p38MAPK members, STAT1 and PARP1 at the mRNA levels. There was an overall reduction of RNA biogenesis of gene members of this pathway suggesting that perhaps these signaling pathways do not function optimally after RAD9 depletion. Using network analysis we found there may be differential activation of transcriptional regulators between the irradiated and bystander cells involving the SP1 and NUPR1 transcription factors. Network analysis also suggested that HIF1a (Hypoxia induced factor 1a) activation could be a negative predictor of the bystander effect and perhaps that local hypoxic stress observed by cells that are directly exposed to radiation may predict whether or not they will elicit a bystander response. Gene expression in H1299 cells was measured at 4 hours after exposure to 1 Gy a-particles. There were two groups based on RAD9 status, RAD9 normal and RAD9 depleted by siRNA. In each of these groups, sham irradiated, direct irradiated cells for positive bystanders, positive bystanders, direct irradiated cells for negative bystanders and negative bystanders; were identified based on micronucleus responses. Five biological replicates were analyzed for each experimental group.

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Human CD4+ memory T cells are preferential targets for bystander activation and apoptosis

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