Expression analysis and functional activity of interleukin-7 splice variants

Abstract

Alternative splicing results in multiple protein isoforms derived from a single gene. The magnitude of this process ranges from a complete loss of function to gain of new function. We examined, as a paradigm, alternative splicing of the non-redundant human cytokine, interleukin-7 (IL-7). We show that extensive IL-7 splicing in human tissues of different histology, including MTB þ granuloma lesions, transformed tissue and tumor cell lines. IL-7 splice variants were expressed as recombinant proteins. A differentially spliced IL-7 isoform, lacking exon 5, leads to STAT-5 phosphorylation in CD4 þ and CD8 þ T cells, promotes thymocyte maturation and T-cell survival. Human tumor lesions show aberrant IL-7 isoform expression, as compared with the autologous, non-transformed tissue. Alternatively spliced cytokines, such as IL-7, represent candidates for diagnostics and therapeutic interventions.

Increased (6 exon) interleukin-7 production after M. tuberculosis infection and soluble interleukin-7 receptor expression in lung tissue

“…NHP physiology may be different when compared with the humans, which is evident based on the differential IL-7 RNA spicing pattern in PBMCs. 7,8 IL7c is the dominant transcript in NHP PBMCs, whereas IL-7d4 is the dominant transcript in human PBMCs. Human and NHP PBMCs show a similar composition of immune cells, except for Tregs and CD8a-a þ T cells.…”

“…6,7,9 IL-7d5, the isoform lacking exon 5, has been demonstrated to be dominantly expressed in granuloma lesions from individuals with latent tuberculosis. 7 This IL-7 isoform acts as an IL-7 agonist in promoting immune cell survival and differentiation of human thymocytes, and it also drives differentiation of human neuronal stem cells.…”

“…6,7,9 IL-7d5, the isoform lacking exon 5, has been demonstrated to be dominantly expressed in granuloma lesions from individuals with latent tuberculosis. 7 This IL-7 isoform acts as an IL-7 agonist in promoting immune cell survival and differentiation of human thymocytes, and it also drives differentiation of human neuronal stem cells. 7,10 More recently, the IL-7R has been demonstrated to be alternatively spliced associated with different haplotypes that affect gene regulation and potentially RNA splicing 8,11 _ENREF_9.…”

“…7 This IL-7 isoform acts as an IL-7 agonist in promoting immune cell survival and differentiation of human thymocytes, and it also drives differentiation of human neuronal stem cells. 7,10 More recently, the IL-7R has been demonstrated to be alternatively spliced associated with different haplotypes that affect gene regulation and potentially RNA splicing 8,11 _ENREF_9. A particular haplotype has been associated with an increased risk of developing multiple sclerosis.…”

“…16 The IL-7R is expressed by a variety of immune 17,18 and non-immune cells, 7,10 either along with the common cytokine g-chain 19 or the receptor for thymic stromal lymphopoietin on dendritic cells. 20 The soluble form of the IL-7R blocks IL-7 activity.…”