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Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[a]pyrene

ABSTRACT: Polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (B[a]P), are widely distributed carcinogenic and immunotoxic environmental contaminants, known to affect T lymphocytes. Despite extensive studies conducted, the molecular targets and pathways involved in their immunotoxic effects in human T lymphocytes remain unknown. Here, we analyzed the gene expression profile of primary human T lymphocytes treated with the prototypical PAH, B[a]P using a microarray-based transcriptome analysis. After a 48-h exposure to B[a]P, we identified 158 genes differentially expressed in T lymphocytes including not only genes well-known to be affected by PAHs such as the cytochromes P450 (CYP) 1A1 and 1B1, and the proto-oncogene c-KIT but also other ones not previously shown to be targeted by B[a]P such as genes encoding the gap junction beta-2 (GJB2) and beta-6 (GJB6) proteins. Functional enrichment analysis revealed that those candidates were significantly associated with the aryl hydrocarbon (AhR) and interferon (IFN) signalling pathways; it also revealed a clear alteration in essential biological functions, mainly those related to T lymphocyte recruitment. These data were confirmed by RT-qPCR assays for some selected genes such as the chemokine (C-C motif) ligand CCL3, and the cell adhesion protein like selectin L (SELL). Using functional tests in transwell migration experiments, B[a]P was shown to significantly decrease the chemokine (C-X-C motif) ligand 12 (CXCL12)-induced chemotaxis and transendothelial migration of T lymphocytes. Overall, the present study opens the way to unsuspected responsive pathway of interest, i.e., T lymphocyte migration, providing a broader understanding of the molecular basis of the immunotoxicity of PAHs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE117527 | GEO | 2018/12/26

REPOSITORIES: GEO

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Project description:Lymphocyte activation and effector state differentiation critically depend on integration of multiple signals, including those from antigen, co-stimulatory ligand and cytokine receptors. Thus, discovery of molecular components and mechanisms underlying signal integration is vital for the understanding and control of adaptive immune responses. Stimulation of antigen receptors in lymphocytes leads to the activation of NFAT family transcription factors (TFs) as well as the inducible expression of the immune-selective IRFs, IRF4 and IRF8; the latter are differentially controlled by co-stimulatory ligand and cytokine receptor signaling. Despite their major overlapping functions in lymphocyte activation and differentiation, it has remained enigmatic if NFATs can perform signal integration with IRF4 and IRF8, via their cooperative assembly on composite genomic regulatory elements. Composite elements (CEs) provide a powerful means of signal integration by inducible TFs and despite their clear importance, CEs arguably remain the least explored elements within cis-regulomes. To test the above hypothesis, we deployed a generalizable computational strategy, which revealed a stereospecific NFAT-IRF composite element (NICE) motif that was enriched within active chromatin regions (H3K27Ac) of activated B and T lymphocytes. NICE containing DNA sequences promoted cooperative binding of NFATs with IRF4 or IRF8. Genomic analyses in activated B cells revealed co-dependent genes that undergo activation or repression and contain NICE motifs in their regulatory regions. Notably, NFATc2 and IRF8 form a positive feedforward loop and coordinately repress the Prdm1 gene by binding a NICE motif in a phylogenetically conserved region, thereby inhibiting extrafollicular plasma cell differentiation and promoting the germinal center fate of activated B cells. The NICE motif is also enriched in DNA sequences located in accessible chromatin of human lymphocytes, suggesting evolutionary conservation of its function. The cooperative assembly of NFAT family members with IRF4 and IRF8 on NICE motifs reveals a new genomic control mechanism that enables signal integration during lymphocyte activation and differentiation.

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Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[a]pyrene

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