Preferential expression of the novel alternative isoform I.3 of hypoxia-inducible factor 1α in activated human T lymphocytes

Abstract

Hypoxia-Inducible Factor 1α (HIF-1α) is critical not only in the regulation of oxygen homeostasis, but also in the regulation of innate and adaptive immune systems. We previously reported that TCRmediated activation of T cells in mice leads to the expression of an alternative isoform of HIF-1α that inhibits activated T cells in a delayed negative feed-back manner. In this paper, we describe a novel mRNA isoform of human HIF-1α that is upregulated in peripheral T lymphocytes after TCR stimulation. This activation-inducible isoform is expressed using the alternative first exon I.3, and it encodes a protein that is 24 amino acids longer than the ubiquitous HIF-1α isoform. This mRNA isoform I.3 of HIF-1α is expressed in a tissue-specific manner with the highest expression found in peripheral blood leukocytes and the thymus.

Adaptive and Maladaptive Cardiorespiratory Responses to Continuous and Intermittent Hypoxia Mediated by Hypoxia-Inducible Factors 1 and 2

“…Utilization of Exon 1.1 generates the ubiquitous isoform, whereas utilization of Exon 1.3 in activated T lymphocytes generates a variant isoform in which the NH 2 -terminal residues prior to the bHLH domain are different from those encoded by Exon 1.1 (204). In HIF-1 α (Ex1.3) the first 12 amino acids of HIF-1 α (Ex1.1) are replaced by a novel 36-amino acid sequence.…”

Interdependence of hypoxic and innate immune responses

“…The activated HIF-deficient T cells showed enhanced proliferation and contributed to blocking bacterial proliferation in a caecal ligation and puncture [G] model of sepsis 46 . The paradoxical behaviour of HIF in activated T cells may derive from alternative splicing and expression of a novel isoform of HIF1α that inhibits cellular activation in a delayed feedback manner 47 . Data from studies involving the deletion of Hif1a specifically in T cells indicates that tight regulation of HIF function in these cells is crucial to prevent cell death, and implies that T cells may have a minor role in hypoxic tissues due to hypoxia-mediated and HIF-dependent cell death 48 .…”

Human and mouse DOCK10 splicing isoforms with alternative first coding exon usage are differentially expressed in T and B lymphocytes

“…Exons 2 to 56 were common to isoforms 1 and 2, although a significant proportion of the cDNA clones were alternatively spliced variants (see below). The variable first exon organization has been proposed as a genetic mechanism for directing distinct cell-and tissue-specific patterns of gene expression [18,19].…”