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Interleukin-2, interleukin-15, and their receptors
T Waldmann1, Y Tagaya, R Bamford
1Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
Both IL-15 and IL-2 are 14-15 kDa members of the four alpha-helical bundle family of cytokines that have T cell growth factor activity. In contrast to the pattern manifested by IL-2, IL-15 mRNA is produced by a wide variety of tissues other than T cells. We have demonstrated that IL-15 expression is posttranscriptionally regulated by multiple elements, including the ten upstream AUGs of the 5' UTR, a 48aa signal peptide and the carboxy-terminus of the mature protein. IL-15 utilizes two distinct receptor signaling pathways. In T cells the IL-15 receptor includes IL-2R beta and gamma c subunits shared with IL-2 as well as an IL-15 specific receptor, IL-15R alpha. However, mast cells respond to IL-15 using a receptor system that does not share elements with the IL-2R system but involves a novel 60-65 kDa IL-15RX subunit. In mast cells, IL-15 signaling involves JAK-2 and STAT-5 activation rather than the JAK-1 and JAK-3 as well as the STAT-3 and STAT-5 used by both IL-2 and IL-15 in activated T cells.
Insights
Interleukin-15 (IL-15) and Interleukin-2 (IL-2) are cytokines with T cell growth factor activity. IL-15, unlike IL-2, is produced by many tissues and uses distinct signaling pathways in T cells and mast cells.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- Interleukin-15 (IL-15) and Interleukin-2 (IL-2) are related cytokines with T cell growth factor activity.
- IL-15 exhibits broader tissue expression compared to IL-2, suggesting diverse regulatory mechanisms.
- Understanding IL-15 signaling is crucial for comprehending immune responses and developing targeted therapies.
Purpose of the Study:
- To investigate the posttranscriptional regulation of IL-15 expression.
- To elucidate the distinct receptor signaling pathways utilized by IL-15 in different cell types, specifically T cells and mast cells.
- To compare the molecular components and signaling cascades of IL-15 and IL-2 receptors.
Main Methods:
- Analysis of IL-15 mRNA expression patterns across various tissues.
- Identification of regulatory elements in the 5' untranslated region (UTR) and protein sequence affecting IL-15 expression.
- Characterization of IL-15 receptor subunits (IL-15R alpha, IL-2R beta, gamma c, IL-15RX) on T cells and mast cells.
- Investigation of downstream signaling pathways, including Janus kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs), in response to IL-15 stimulation.
Main Results:
- IL-15 mRNA is expressed in a wide array of tissues beyond T cells.
- Posttranscriptional regulation of IL-15 involves elements such as upstream AUGs, a signal peptide, and the mature protein's carboxy-terminus.
- T cells utilize a receptor complex including IL-2R beta, gamma c, and IL-15R alpha for IL-15 signaling.
- Mast cells employ a distinct IL-15 receptor system involving IL-15RX and activate JAK-2/STAT-5 signaling, differing from the JAK-1/JAK-3/STAT-3/STAT-5 pathway in T cells.
Conclusions:
- IL-15 expression is subject to complex posttranscriptional control.
- IL-15 signals through divergent receptor complexes and downstream pathways in T cells versus mast cells.
- These findings highlight the multifaceted nature of IL-15 signaling and its differential impact on immune cell function.