Interleukin 15

[5] IL-15 LSP isoform was identified in Golgi apparatus [GC], early endosomes and in the endoplasmic reticulum (ER).

On the other hand, IL-15 SSP isoform is not secreted and it appears to be restricted to the cytoplasm and nucleus where plays an important role in the regulation of cell cycle.

The isoform which had an alternative exon 5 containing another 3' splicing site, exhibited a high translational efficiency, and the product lack hydrophobic domains in the signal sequence of the N-terminus.

[13] Expression of IL-15 can be stimulated by cytokine such as GM-CSF, double-strand mRNA, unmethylated CpG oligonucleotides, lipopolysaccharide (LPS) through Toll-like receptors (TLR), interferon gamma (IFN-γ) or after infection of monocytes herpes virus, Mycobacterium tuberculosis and Candida albicans (Figure 2).

It also activates phosphatidylinositol 3-kinase (PI3K) and AKT signaling pathway and induce expression of transcription factors including c-Fos, c-Jun, c-Myc and NF-κB.

[10] In humans with celiac disease IL-15 similarly suppresses apoptosis in T-lymphocytes by inducing Bcl-2 and/or Bcl-xL.

When IL-15 binds its receptor, JAK kinase, STAT3, STAT5, and STAT6 transcription factors are activated to elicit downstream signaling events.

IL-15 and its receptor subunit alpha (IL-15Rα) are also produced by skeletal muscle in response to different exercise doses (myokine), playing significant roles in visceral (intra-abdominal or interstitial) fat reduction [20][21] and myofibrillar protein synthesis (hypertrophy).

[22] All classes of jawed vertebrates, including sharks, share an IL-15 gene at a conserved genomic location.

[23] Unusual features of IL-15 that appear to be conserved throughout jawed vertebrate evolution are (1) multiple AUGs in the transcript 5’ untranslated region,[14][24] (2) an unusually long N-terminal hydrophobic (leader) sequence,[14][23] and (3) a dependency on the formation of what might be considered “heterodimer cytokine” complexes with IL-15Rα for stability.

[25] The latter probably helps to retain IL-15 activity at the surface of the expressing cell and therefore within restricted tissue niches, while the reasons for (1) and (2) are still not known.

[32] There have been recent studies suggesting that suppression of IL-15 may be a potential treatment for celiac disease and even presents the possibility of preventing its development.

[35] A recent study found IL-15 present in the synovial tissue of patients diagnosed with rheumatoid arthritis.

[39] Vector-based therapy – Nonlytic Newcastle Disease Virus (NDV) was engineered to express recombinant IL-15 protein to generate an NDV-modified tumor vaccine.

[40] A recombinant vaccinia virus expressing influenza A proteins and IL-15 promoted cross protection by CD4+ T cells.

[41] While influenza A virus expressing IL-15 stimulates both innate and adaptive immune cells to decrease tumor growth mice.

[46] Nogapendekin alfa inbakicept (ALT-803) is an IL-15 superagonist complex IL-15N72D:IL-15RαSu/Fc that includes an IL-15 mutant (IL-15N72D) and a dimeric IL-15 receptor α sushi domain-IgG1 Fc fusion protein.

[47][48] ALT-803 was given fast track status by the FDA in 2017 and at that time, Phase III trials in bladder cancer were being prepared.

This fusion protein, referred to as protein receptor-linker-IL-15 (RLI-15) acts as an IL-15 superagonists specifically binding with high affinity the mid-affinity IL-2/IL-15 receptor formed by IL2RB and the Common gamma chain (γc or CD132), that has an increased serum half-life and biological activity similar to complexed IL-15/IL-15Rα-Fc.

Figure 1. IL-15 is 14–15 kDa glycoprotein encoded by the 34 kb region on chromosome 4q31, and by central region of chromosome 8 in mice. The human IL-15 gene comprises nine exons (1–8 and 4A) and eight introns, four of which (exons 5 through 8) code for the mature protein.
Figure 2. The originally identified isoform, with long signal peptide of 48 amino acids (IL-15 LSP) consisted of a 316 bp 5'-untraslated region (UTR), 486 bp coding sequence and on the C-terminus 400 bp 3'-UTR region. The other isoform (IL-15 SSP) has a short signal peptide of 21 amino acids encoded by exons 4A and 5. Both isoforms shared 11 amino acids between signal sequences of the leader peptides.
Figure 3. The main mechanism of IL-15 signaling is trans-presentation which is mediated by membrane-bound complex IL-15/IL-15Rα. Signaling pathway of IL-15 begins with binding to IL-15Rα receptor, with subsequent presentation to surrounding cells bearing IL-15Rβγc complex on their cell surface.
Figure 4. IL-15 bind to IL-15Rα receptor alone with affinity (K a = 1.10 11 /M). It can also bind to IL-15Rβγc signaling complex with lower affinity (Ka = 1.10 9 /M).
Figure 5. Signaling pathway of IL-15 begins with binding to IL-15Rα receptor, with subsequent presentation to surrounding cells bearing IL-15Rβγc complex on their cell surface. Upon binding IL-15β subunit activates Janus kinase 1 (Jak1) and γc subunit Janus kinase 3 (Jak3), which leads to phosphorylation and activation of signal transducer and activator of transcription 3 (STAT3) and STAT5. Due to sharing of receptor subunits between IL-2 and IL-15, both of these cytokines have similar downstream effects including the induction of B-cell lymphoma (Bcl-2), MAP (mitogen-activated protein kinase) kinase pathway and the phosphorylation of Lck (lymphocyte-activated protein tyrosine kinase) and Syk (spleen tyrosine kinase) kinases, which leads to cell proliferation and maturation.
Figure 6. The second mechanism of IL-15 action is cis-presentation, when IL-15 is presented by IL-15Rα to 15Rβγc signaling complex on the same cell. This mechanism is mediated by the C-terminus flexibility which is mediated by 32 amino acids linker and/or 74 amino acids long PT region.