Interleukin-15 (IL-15) is aprotein that in humans is encoded by the IL15gene. IL-15 is an inflammatorycytokine with structural similarity to Interleukin-2 (IL-2). Like IL-2, IL-15 binds to and signals through a complex composed of IL-2/IL-15 receptor beta chain (CD122) and thecommon gamma chain (gamma-C, CD132). IL-15 is secreted bymononuclear phagocytes (and some other cells) following infection byvirus(es). This cytokine induces theproliferation ofnatural killer cells, i.e. cells of theinnate immune system whose principal role is to kill virally infected cells.
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.
IL-15 is 14–15 kDaglycoprotein encoded by the 34 kb region ofchromosome 4q31 in humans, and at the central region ofchromosome 8 inmice.[10] The human IL-15gene comprises nineexons (1–8 and 4A) and eightintrons, four of which (exons 5 through 8) code for the matureprotein (Figure 1).[11]
Two alternatively spliced transcript variants of thisgene encoding the sameprotein have been reported.[12] The originally identifiedisoform, with longsignal peptide of 48amino acids (IL-15 LSP) consisted of a 316 bp5'-untranslated region (UTR), 486 bpcoding sequence and the C-terminus 400 bp3'-UTR region. The other isoform (IL-15 SSP) has a short signal peptide of 21 amino acids encoded byexons 4A and 5.[11] Both isoforms shared 11 amino acids betweensignal sequences of the N-terminus.[13] Although both isoforms produce the same mature protein, they differ in theircellular trafficking.[11] IL-15 LSP isoform was identified inGolgi apparatus [GC], earlyendosomes and in theendoplasmic reticulum (ER). It exists in two forms, secreted and membrane-bound particularly ondendritic cells. On the other hand, IL-15 SSP isoform is not secreted and it appears to be restricted to thecytoplasm andnucleus where plays an important role in the regulation ofcell cycle.[11]
It has been demonstrated that two isoforms of IL-15 mRNA are generated by alternativesplicing in mice. The isoform which had an alternative exon 5 containing another 3' splicing site, exhibited a hightranslational efficiency, and the product lackhydrophobicdomains in thesignal sequence of the N-terminus. This suggests that the protein derived from this isoform is located intracellulary. The other isoform with normal exon 5, which is generated by integral splicing of the alternative exon 5, may be released extracellulary.[14]
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 (Ka = 1.1011/M). It can also bind to IL-15Rβγc signaling complex with lower affinity (Ka = 1.109/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.
The prevailing mechanism of IL-15 action seems to bejuxtacrine signaling or also determined as cell-to-cell contact. It also includes intracrine and reverse signaling. IL-15 was initially characterized as a soluble molecule. Later it was shown that IL-15 also exists as a membrane-bound form which represents the major form of IL-15protein. In membrane-bound form it could be bound directly tocellular membrane or presented byIL-15Rα receptor.[15]
The main mechanism of IL-15 signaling is trans-presentation which is mediated by membrane-bound complex IL-15/IL-15Rα (Figure 3).[17] IL-15 bind to IL-15Rα receptor alone with anaffinity ofKa = 1.1011/M. It can also bind to IL-15Rβγc signaling complex with lower affinity (Ka = 1.109/M) (Figure 4).[9]
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 activatesJanus kinase 1 (Jak1) and γc subunitJanus kinase 3 (Jak3), which leads tophosphorylation and activation ofsignal transducer and activator of transcription 3 (STAT3) andSTAT5.[18] Due to sharing ofreceptor subunits betweenIL-2 and IL-15, both of thesecytokines have similar downstream effects including the induction ofBcl-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 5).[9][19]
Inmast cells, the IL-15Rsignaling pathway has been found to include Jak2 and STAT5 instead Jak1/3 and STAT3/5. Phosphorylation STATs form transcription factors and activate transcription of appropriate genes. The β chain of IL-15R recruits and also activates protein tyrosine kinases of the Src family including Lck, Fyn and Lyn kinase. 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.[15]
IL-15 is also able to bind to the 15Rβγc signaling complex with intermediate affinity without requirement for IL-15Rα receptor. Upon binding IL-15 to signaling complex, kinases of the Src family including Lck and Fyn are activated, and subsequently activates PI3K andMAPK signaling pathway.[20] 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 (Figure 6).[17]
IL-15 regulates the activation and proliferation ofT andnatural killer (NK) cells. Survival signals that maintain memory T cells in the absence of antigen are provided by IL-15. This cytokine is also implicated in NK cell development. In rodent lymphocytes, IL-15 preventsapoptosis by inducingBCL2L1/BCL-x(L), an inhibitor of the apoptosis pathway.[12] In humans withceliac disease IL-15 similarly suppresses apoptosis in T-lymphocytes by inducingBcl-2 and/orBcl-xL.[21]
Ahematopoietin receptor, theIL-15 receptor, that binds IL-15 propagates its function. Some subunits of the IL-15 receptor are shared in common with the receptor for a structurally related cytokine calledInterleukin 2 (IL-2) allowing both cytokines to compete for and negatively regulate each other's activity.CD8+ memory T cell number is controlled by a balance between IL-15 and IL-2. When IL-15 binds its receptor,JAK kinase,STAT3,STAT5, andSTAT6transcription 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[22][23] and myofibrillar protein synthesis (hypertrophy).[24]
All classes of jawed vertebrates, including sharks, share anIL-15 gene at a conserved genomic location.[25] Unusual features of IL-15 that appear to be conserved throughout jawed vertebrate evolution are (1) multiple AUGs in the transcript 5' untranslated region,[16][26] (2) an unusually long N-terminal hydrophobic (leader) sequence,[16][25] and (3) a dependency on the formation of what might be considered "heterodimer cytokine" complexes with IL-15Rα for stability.[27] 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. In fish, the gene duplication resulting in mammalian IL-2Rα and IL-15Rα[28] has not occurred yet,[29][30] and the molecules IL-2, IL-15, andIL-15-like (IL-15L) all share the same receptor alpha chain[27][31] which looks like mammalian IL-15Rα.[29][32] In fish, as in mammals, IL-15 appears to stimulate type 1 (Th1) immunity.[26][27][33]
In jawless fish or invertebrates, homologues of IL-15 have not been found.
In humans with history of acuteinfectious mononucleosis (the syndrome associated with primaryEpstein–Barr virus infection), IL-15R expressing lymphocytes are not detected even 14 years after infection.[34]
There have been recent studies suggesting that suppression of IL-15 may be a potential treatment forceliac disease and even presents the possibility of preventing its development. In one study with mice blocking IL-15 with an antibody led to the reversal of autoimmune intestinal damage.[35] In another study mice used were able to eatgluten without developing symptoms.[36]
A recent study found IL-15 present in the synovial tissue of patients diagnosed with rheumatoid arthritis. Preliminary research has functionally implicated IL-15 role in collagen-induced arthritis.[38]
Vector-based therapy – Nonlytic Newcastle Disease Virus (NDV) was engineered to express recombinant IL-15 protein to generate an NDV-modified tumor vaccine. Preclinical results of NDV-modified tumor vaccine showed promise by controlling melanoma tumor growth in mice.[42] A recombinant vaccinia virus expressing influenza A proteins and IL-15 promoted cross protection by CD4+ T cells.[43] A Brucella DNA vaccine containing IL-15 gene enhanced the CD8+ T cell immune response in mice.[44] IL-15 was needed for CD4+ T cell heterosubtypic protection while using a multivalent influenza vaccine using vaccinia-based vector.[43] While influenza A virus expressing IL-15 stimulates both innate and adaptive immune cells to decrease tumor growth mice.[45]
Currently there are two varieties of IL-15 superagonist available. One combines IL-15 and IL-15Rα-Fc (R&D Systems)in vitro to generate the complex. It is referred to as IL-15 SA. A second IL-15 superagonist complex called ALT-803 is offered by Altor BioScience.
IL-15 SA is currently being evaluated for antiviral and anticancer activities, in addition to enhancing immunotherapy and vaccination.[46][47] One potential shortcoming of IL-15 SA was its enhancement of septic shock in mice.[48]
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.[49][50]
ALT-803 was givenfast track status by the FDA in 2017 and at that time, Phase III trials in bladder cancer were being prepared.
Nanrilkefusp alfa (RLI-15) is a fusion protein consisting of the NH2-terminal (amino acids 1–77, sushi+) cytokine-binding domain ofIL-15Rα coupled to IL-15 via a 20-amino acid flexible linker. 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 byIL2RB and theCommon gamma chain (γc orCD132), that has an increased serum half-life and biological activity similar to complexed IL-15/IL-15Rα-Fc. RLI-15 demonstrated a strong anti-tumor effect in two different tumor models.[51] RLI-15 is being produced and tested by Cytune Pharma affiliated company ofSOTIO which renamed it to SO-C101, later to SOT101.[52] Phase 1 trial was initiated in 2019.[53]
Possible implications of IL-15 treatment for individuals diagnosed with rheumatoid arthritis (RA). HuMax-IL15 was derived from transgenic mice and individuals with RA underwent HuMax-IL15 administration for twelve weeks. After treating synovial tissue with HuMax-IL15, decreased proliferation of interferon-y and suppressed expression of CD69 was observed. Additionally, 63% of patients reported a 20% improvement while 25% of patients reported a 70% improvement. American College of Rheumatology criteria were used to determine the severity of RA symptoms.[38]
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