Interleukin-7 (IL7) is produced primarily by T zone fibroblastic reticular cells found in lymphoid organs, and also expressed by non-hematopoietic stromal cells present in other tissues including the skin, intestine and liver. It is an essential survival factor for lymphocytes, playing a key anti-apoptotic role in T-cell development, as well as mediating peripheral T-cell maintenance and proliferation. This dual function is reflected in a dose-response relationship that distinguishes the survival function from the proliferative activity; low doses of IL7 (<1 ng/ml) sustain only survival, higher doses (>1 ng/ml) promote survival and cell cycling (Kittipatarin et al. 2006, Swainson et al. 2007).
The IL7 receptor is a heterodimeric complex of the the common cytokine-receptor gamma chain (IL2RG, CD132, or Gc) and the IL7-receptor alpha chain (IL7RA, IL7R, CD127). Both chains are members of the type 1 cytokine family. Neither chain is unique to the IL7 receptor as IL7RA is utilized by the receptor for thymic stromal lymphopoietin (TSLP) while Gc is shared with the receptors for IL2, IL4, IL9, IL15 and IL21. Gc consists of a single transmembrane region and a 240aa extracellular region that includes a fibronectin type III (FNIII) domain thought to be involved in receptor complex formation. It is expressed on most lymphocyte populations. Null mutations of Gc in humans cause X-linked severe combined immunodeficiency (X-SCID), which has a phenotype of severely reduced T-cell and natural killer (NK) cell populations, but normal numbers of B cells. In addition to reduced T- and NK-cell numbers Gc knockout mice also have dramatically reduced B-cell populations suggesting that Gc is more critical for B-cell development in mice than in humans. Patients with severe combined immunodeficiency (SCID) phenotype due to IL7RA mutations (see Puel & Leonard 2000), or a partial deficiency of IL7RA (Roifman et al. 2000) have markedly reduced circulating T cells, but normal levels of peripheral blood B cells and NK cells, similar to the phenotype of Gc mutations, highlighting a requirement for IL7 in T cell lymphopoiesis. It has been suggested that IL7 is essential for murine, but not human B cell development, but recent studies indicate that IL7 is essential for human B cell production from adult bone marrow and that IL7-induced expansion of the progenitor B cell compartment is increasingly critical for human B cell production during later stages of development (Parrish et al. 2009).
IL7 has been shown to induce rapid and dose-dependent tyrosine phosphorylation of JAKs 1 and 3, and concomitantly tyrosine phosphorylation and DNA-binding activity of STAT5a/b (Foxwell et al. 1995). IL7RA was shown to directly induce the activation of JAKs and STATs by van der Plas et al. (1996). Jak1 and Jak3 knockout mice displayed severely impaired thymic development, further supporting their importance in IL7 signaling (Rodig et al. 1998, Nosaka et al. 1995).
The role of STAT5 in IL7 signaling has been studied largely in mouse models. Tyr449 in the cytoplasmic domain of IL7RA is required for T-cell development in vivo and activation of JAK/STAT5 and PI3k/Akt pathways (Jiang et al. 2004, Pallard et al. 1999). T-cells from an IL7RA Y449F knock-in mouse did not activate STAT5 (Osbourne et al. 2007), indicating that IL7 regulates STAT5 activity via this key tyrosine residue. STAT5 seems to enhance proliferation of multiple cell lineages in mouse models but it remains unclear whether STAT5 is required solely for survival signaling or also for the induction of proliferative activity (Kittipatarin & Khaled, 2007).
The model for IL7 receptor signaling is presumed to resemble that of other Gc family cytokines, based on detailed studies of the IL2 receptor, where IL2RB binds constitutively to JAK1 while JAK3 is pre-associated uniquely with the Gc chain. Extending this model to IL7 suggests a similar series of events: IL7RA constitutively associated with JAK1 binds IL7, the resulting trimer recruits Gc:JAK3, bringing JAK1 and JAK3 into proximity. The association of both chains of the IL7 receptor orients the cytoplasmic domains of the receptor chains so that their associated kinases (Janus and phosphatidylinositol 3-kinases) can phosphorylate sequence elements on the cytoplasmic domains (Jiang et al. 2005). JAKs have low intrinsic enzymatic activity, but after mutual phosphorylation acquire much higher activity, leading to phosphorylation of the critical Y449 site on IL7RA. This site binds STAT5 and possibly other signaling adapters, they in turn become phosphorylated by JAK1 and/or JAK3. Phosphorylated STATs translocate to the nucleus and trigger the transcriptional events of their target genes.
The role of the PI3K/AKT pathway in IL7 signaling is controversial. It is a potential T-cell survival pathway because in many cell types PI3K signaling regulates diverse cellular functions such as cell cycle progression, transcription, and metabolism. The ERK/MAPK pathway does not appear to be involved in IL7 signaling (Crawley et al. 1996).
It is not clear how IL7 influences cell proliferation. In the absence of a proliferative signal such as IL7 or IL3, dependent lymphocytes arrest in the G0/G1 phase of the cell cycle. To exit this phase, cells typically activate specific G1 Cyclin-dependent kinases/cyclins and down regulate cell cycle inhibitors such as Cyclin-dependent kinase inhibitor 1B (Cdkn1b or p27kip1). There is indirect evidence suggesting a possible role for IL7 stimulated activation of PI3K/AKT signaling, obtained from transformed cell lines and thymocytes, but not confirmed by observations using primary T-cells (Kittipatarin & Khaled, 2007). IL7 withdrawal results in G1/S cell cycle arrest and is correlated with loss of cdk2 activity (Geiselhart et al. 2001), both events which are known to be regulated by the dephosphorylating activity of Cdc25A. Expression of a p38 MAPK-resistant Cdc25A mutant in an IL-7-dependent T-cell line as well as in peripheral, primary T-cells was sufficient to sustain cell survival and promote cell cycling for several days in the absence of IL-7 (Khaled et al. 2005). Cdkn1b is a member of the CIP/KIP family of cyclin-dependent cell cycle inhibitors (CKIs) that negatively regulates the G1/S transition. In IL7 dependent T-cells, the expression of Cdkn1b was sufficient to cause G1 arrest in the presence of IL7. Withdrawal of IL7 induced the upregulation of Cdkn1b and arrested cells in G1 while siRNA knockout of Cdkn1b enhanced cell cycle progression. However, adoptive transfer of Cdkn1b-deficient lymphocytes into IL7 deficient mice indicated that loss of Cdkn1b could only partially compensate for the IL7 signal needed by T-cells to expand in a lymphopenic environment (Li et al. 2006), so though Cdkn1b may be involved in negative regulation of the cell cycle through an effect on cdk2 activity, its absence is not sufficient to fully induce cell cycling under lymphopenic conditions.
Lin JX, Migone TS, Tsang M, Friedmann M, Weatherbee JA, Zhou L, Yamauchi A, Bloom ET, Mietz J, John S.; ''The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15.''; PubMedEurope PMCScholia
Noguchi M, Nakamura Y, Russell SM, Ziegler SF, Tsang M, Cao X, Leonard WJ.; ''Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor.''; PubMedEurope PMCScholia
Zhu MH, Berry JA, Russell SM, Leonard WJ.; ''Delineation of the regions of interleukin-2 (IL-2) receptor beta chain important for association of Jak1 and Jak3. Jak1-independent functional recruitment of Jak3 to Il-2Rbeta.''; PubMedEurope PMCScholia
Ye SK, Agata Y, Lee HC, Kurooka H, Kitamura T, Shimizu A, Honjo T, Ikuta K.; ''The IL-7 receptor controls the accessibility of the TCRgamma locus by Stat5 and histone acetylation.''; PubMedEurope PMCScholia
Ghazawi FM, Faller EM, Parmar P, El-Salfiti A, MacPherson PA.; ''Suppressor of cytokine signaling (SOCS) proteins are induced by IL-7 and target surface CD127 protein for degradation in human CD8 T cells.''; PubMedEurope PMCScholia
Wei C, Lai L, Goldschneider I.; ''Pre-pro-B cell growth-stimulating factor (PPBSF) upregulates IL-7Ralpha chain expression and enables pro-B cells to respond to monomeric IL-7.''; PubMedEurope PMCScholia
Yu CR, Young HA, Ortaldo JR.; ''Characterization of cytokine differential induction of STAT complexes in primary human T and NK cells.''; PubMedEurope PMCScholia
Juffroy O, Bugault F, Lambotte O, Landires I, Viard JP, Niel L, Fontanet A, Delfraissy JF, Thèze J, Chakrabarti LA.; ''Dual mechanism of impairment of interleukin-7 (IL-7) responses in human immunodeficiency virus infection: decreased IL-7 binding and abnormal activation of the JAK/STAT5 pathway.''; PubMedEurope PMCScholia
Foxwell BM, Beadling C, Guschin D, Kerr I, Cantrell D.; ''Interleukin-7 can induce the activation of Jak 1, Jak 3 and STAT 5 proteins in murine T cells.''; PubMedEurope PMCScholia
Kondo M, Takeshita T, Higuchi M, Nakamura M, Sudo T, Nishikawa S, Sugamura K.; ''Functional participation of the IL-2 receptor gamma chain in IL-7 receptor complexes.''; PubMedEurope PMCScholia
Chi F, Chen L, Wang C, Li L, Sun X, Xu Y, Ma T, Liu K, Ma X, Shu X.; ''JAK3 inhibitors based on thieno[3,2-d]pyrimidine scaffold: design, synthesis and bioactivity evaluation for the treatment of B-cell lymphoma.''; PubMedEurope PMCScholia
Flanagan ME, Blumenkopf TA, Brissette WH, Brown MF, Casavant JM, Shang-Poa C, Doty JL, Elliott EA, Fisher MB, Hines M, Kent C, Kudlacz EM, Lillie BM, Magnuson KS, McCurdy SP, Munchhof MJ, Perry BD, Sawyer PS, Strelevitz TJ, Subramanyam C, Sun J, Whipple DA, Changelian PS.; ''Discovery of CP-690,550: a potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection.''; PubMedEurope PMCScholia
Nelson BH, Lord JD, Greenberg PD.; ''Cytoplasmic domains of the interleukin-2 receptor beta and gamma chains mediate the signal for T-cell proliferation.''; PubMedEurope PMCScholia
Stanton ML, Brodeur PH.; ''Stat5 mediates the IL-7-induced accessibility of a representative D-Distal VH gene.''; PubMedEurope PMCScholia
Gaffen SL, Lai SY, Ha M, Liu X, Hennighausen L, Greene WC, Goldsmith MA.; ''Distinct tyrosine residues within the interleukin-2 receptor beta chain drive signal transduction specificity, redundancy, and diversity.''; PubMedEurope PMCScholia
Mandal M, Hamel KM, Maienschein-Cline M, Tanaka A, Teng G, Tuteja JH, Bunker JJ, Bahroos N, Eppig JJ, Schatz DG, Clark MR.; ''Histone reader BRWD1 targets and restricts recombination to the Igk locus.''; PubMedEurope PMCScholia
Goodwin RG, Friend D, Ziegler SF, Jerzy R, Falk BA, Gimpel S, Cosman D, Dower SK, March CJ, Namen AE.; ''Cloning of the human and murine interleukin-7 receptors: demonstration of a soluble form and homology to a new receptor superfamily.''; PubMedEurope PMCScholia
Johnston JA, Bacon CM, Finbloom DS, Rees RC, Kaplan D, Shibuya K, Ortaldo JR, Gupta S, Chen YQ, Giri JD.; ''Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15.''; PubMedEurope PMCScholia
van der Plas DC, Smiers F, Pouwels K, Hoefsloot LH, Löwenberg B, Touw IP.; ''Interleukin-7 signaling in human B cell precursor acute lymphoblastic leukemia cells and murine BAF3 cells involves activation of STAT1 and STAT5 mediated via the interleukin-7 receptor alpha chain.''; PubMedEurope PMCScholia
Sharfe N, Roifman CM.; ''Differential association of phosphatidylinositol 3-kinase with insulin receptor substrate (IRS)-1 and IRS-2 in human thymocytes in response to IL-7.''; PubMedEurope PMCScholia
Fantin VR, Sparling JD, Slot JW, Keller SR, Lienhard GE, Lavan BE.; ''Characterization of insulin receptor substrate 4 in human embryonic kidney 293 cells.''; PubMedEurope PMCScholia
Clark JD, Flanagan ME, Telliez JB.; ''Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases.''; PubMedEurope PMCScholia
Reche PA, Soumelis V, Gorman DM, Clifford T, Liu Mr, Travis M, Zurawski SM, Johnston J, Liu YJ, Spits H, de Waal Malefyt R, Kastelein RA, Bazan JF.; ''Human thymic stromal lymphopoietin preferentially stimulates myeloid cells.''; PubMedEurope PMCScholia
Huang H, Rambaldi I, Daniels E, Featherstone M.; ''Expression of the Wdr9 gene and protein products during mouse development.''; PubMedEurope PMCScholia
Lai L, Goldschneider I.; ''Cutting edge: Identification of a hybrid cytokine consisting of IL-7 and the beta-chain of the hepatocyte growth factor/scatter factor.''; PubMedEurope PMCScholia
Kim B, Cheng HL, Margolis B, Feldman EL.; ''Insulin receptor substrate 2 and Shc play different roles in insulin-like growth factor I signaling.''; PubMedEurope PMCScholia
Barata JT, Silva A, Brandao JG, Nadler LM, Cardoso AA, Boussiotis VA.; ''Activation of PI3K is indispensable for interleukin 7-mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells.''; PubMedEurope PMCScholia
Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D, Felletar I, Volkmer R, Müller S, Pawson T, Gingras AC, Arrowsmith CH, Knapp S.; ''Histone recognition and large-scale structural analysis of the human bromodomain family.''; PubMedEurope PMCScholia
Cheng Y, Chikwava K, Wu C, Zhang H, Bhagat A, Pei D, Choi JK, Tong W.; ''LNK/SH2B3 regulates IL-7 receptor signaling in normal and malignant B-progenitors.''; PubMedEurope PMCScholia
Changelian PS, Flanagan ME, Ball DJ, Kent CR, Magnuson KS, Martin WH, Rizzuti BJ, Sawyer PS, Perry BD, Brissette WH, McCurdy SP, Kudlacz EM, Conklyn MJ, Elliott EA, Koslov ER, Fisher MB, Strelevitz TJ, Yoon K, Whipple DA, Sun J, Munchhof MJ, Doty JL, Casavant JM, Blumenkopf TA, Hines M, Brown MF, Lillie BM, Subramanyam C, Shang-Poa C, Milici AJ, Beckius GE, Moyer JD, Su C, Woodworth TG, Gaweco AS, Beals CR, Littman BH, Fisher DA, Smith JF, Zagouras P, Magna HA, Saltarelli MJ, Johnson KS, Nelms LF, Des Etages SG, Hayes LS, Kawabata TT, Finco-Kent D, Baker DL, Larson M, Si MS, Paniagua R, Higgins J, Holm B, Reitz B, Zhou YJ, Morris RE, O'Shea JJ, Borie DC.; ''Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor.''; PubMedEurope PMCScholia
Rosenthal LA, Winestock KD, Finbloom DS.; ''IL-2 and IL-7 induce heterodimerization of STAT5 isoforms in human peripheral blood T lymphoblasts.''; PubMedEurope PMCScholia
There are five variants of the PI3K regulatory subunit, designated p85alpha, p55alpha, p50alpha, p85beta and p55gamma (there are also three variants of the p110 catalytic subunit designated p110alpha, beta, or delta). The first three regulatory subunits are all splice variants of PIK3R1 (p85 or regulatory subunit alpha), the other two are expressed by PIK3R2 and PIK3R3, known as p85 beta, and p55 gamma, respectively. The most highly expressed regulatory subunit is p85alpha. The 3 variants forms of p85 alpha are not explicitly represented in this set.
Studies using chemical crosslinking and monoclonal antibodies specific for the IL-2 receptor gamma chain (Gc) demonstrated that Gc participates in the functional high-affinity interleukin-7 receptor complex (Noguchi et al. 1993, Kondo et al. 1994).
The membrane-associated Gc chain interacts with the intermediate 1:1 IL7:IL7R complex, forming the active ternary complex, which binds IL7 with a 3-fold higher affinity (Kd =80 pM).
IL7 receptor signaling is presumed to resemble that of other Gc family cytokines, based on detailed studies of the IL2 receptor. Extending this model to IL7 suggests a similar series of events that bring JAK1 and JAK3 into proximity within a complex IL7:IL7RA:JAK1:Gc:JAK3. Cytoplasmic domains of the IL7 receptor chains orient so that their associated kinases (Janus and possibly phosphatidylinositol 3-kinases) can phosphorylate sequence elements on the cytoplasmic domains (Jiang et al. 2005).
Tyr449 in the cytoplasmic domain of IL7RA is required for T-cell development in vivo and for activation of the JAK/STAT5 and PI3K/Akt pathways (Jiang et al. 2004, Pallard et al. 1999). Phosphorylated Tyr449 is believed to be a docking site for STAT5 and possibly PI3K, which are then activated by JAKs (Lin et al. 1995, Jiang et al. 2004). T-cells from an IL7RA Y449F knock-in mouse did not activate STAT5 (Osbourne et al. 2007), indicating that IL7 regulates STAT5 activity via this key tyrosine. It is thought that JAK1 phosphorylates IL7RA (Jiang et al. 2004).
Multiple observations support a role for IL7-stimulated JAK/STAT signaling. IL7 induces rapid and dose-dependent tyrosine phosphorylation of JAKs 1 and 3, with concomitant tyrosine phosphorylation and DNA-binding activity of STAT5a/b (Foxwell et al. 1995). IL7RA was shown to directly induce the activation of JAKs and STATs 1, 5, and 3 by van der Plas et al. (1996). In primary human T cells and NK cells, IL7 induced activation of STAT5a, STAT5b and to a lesser extent STAT1 and STAT3 (Yu et al. 1998). Jak1 and Jak3 knockout mice displayed severely impaired thymic development, further supporting their importance in IL7 signaling (Rodig et al. 1998, Nosaka et al. 1995).
In human thymocytes, IL7 activates STAT5. It is thought that phosphorylated Y449 in the cytoplasmic domain of the IL7RA is a docking site for STAT5 (Pallard et al. 1999). STAT5 can be activated in COS 7 cells when co transfected with JAK3 (Lin et al. 1996), though this does not demonstrate that JAK3 phosphorylates STAT5 proteins in response to IL7 in vivo (Lin & Leonard, 2000); it is not clear which JAK kinase phosphorylates STAT5 in vivo. T-cells from an IL7RA Y449F knock-in mouse did not activate STAT5 (Osbourne et al. 2007), indicating that Tyr449 is a key residue regulating IL7 mediated STAT5 activation. STAT3 is critical for early B cell differentiation, but the details of its involvement are unclear (Chou et al 2006).
Interleukin-7 receptor alpha chain (IL7R) binds interleukin-7 (IL7), forming a stable 1:1 IL7:IL7R complex, with a dissociation constant (Kd) of approximately 200 pM (Goodwin et al. 1990, Park et al. 1990). The full-length IL7R is a 439-residue single-pass transmembrane glycoprotein consisting of three domains: a 219-residue extracellular domain (ECD), a 25-residue transmembrane domain and a 195-residue cytoplasmic domain. The ECD belongs to the cytokine receptor homology class 1 (CRH1) family, consisting of two fibronectin type III (FNIII) domains with three potential disulfide bonds in the N-terminal FNIII domain and a WSXWS primary sequence motif in the C-terminal domain (Bazan, 1990). Recruitment of kinases to the cytoplasmic tail of IL7R is required for signal transduction because the intracellular portion of IL7R does not contain intrinsic tyrosine kinase activity. IL7 interacts directly with the extracellular region of IL7R and this leads to the recruitment of the Interleukin receptor common gamma chain (Gc, IL2R) and formation of a receptor complex. IL7 binds glycosylated IL7R 300-fold more tightly than unglycosylated. It is thought that IL7 interacts with both IL7R and Gc in the final complex (McElroy et al. 2007).
The p85 subunit of PI3K binds to phosphorylated Tyr-449 on IL7RA; Y449F substitution inhibits PI3K-dependent proliferation of IL7-stimulated murine B-lineage cells (Venkitaraman & Cowling 1994).
Stimulation of human lymphocyte precursor cells with IL-7 induced tyrosine phosphorylation of the p85 subunit of PI3-kinase (PI3K) and activation of PI3K kinase activity (Dadi et al. 1994). It is thought that, depending on species differences and stage of lymphocyte development, IL7 induced PI3K pathway can promote signals that are important for survival and proliferation of both T cells and B cells.
Activation of PI3K leads to the generation of membrane associated PIP3 and membrane recruitment of AKT/PKB, the key downstream target of PI3K. AKT mediates phosphorylation of downstream substrates involved in regulation of cell survival and proliferation. IL7 induced activation of PI3K/AKT in human thymocytes has been reported (Pallard et al. 1999; Johnson et al. 2008). In mouse thymocytes IL7 stimulation resulted in the inactivation of BAD by serine phosphorylation; the PI3K/AKT pathway has been implicated in BAD phosphorylation. These results suggest that IL7 signaling via AKT inactivates the pro-apoptotic protein BAD promoting T cell survival (Li et al. 2004).
Rochman et al. (2009) suggest that IL7 promotes lymphocyte survival by activating the pro-survival PI3K/AKT signaling pathway and by increasing the expression of survival factors such as BCL2 and myeloid cell leukemia sequence 1 (MCL-1) while iinhibiting the expression of pro-apoptotic factors BAX and BAD.
IL7RA has the small juxta-membrane "Box1" motif, conserved throughout the type I cytokine receptor family (Murakami et al. 1991). This is believed to be the site of JAK1 binding (Tanner et al. 1995); deletion of Box1 eliminates JAK1 phosphorylation (Jiang et al. 2004). Studies with T-cell lines expressing mutant IL-4/IL-7 chimeric receptors revealed that loss of Box1 results in rapid cell death, while Y449F mutation causes cell cycle arrest that precedes cell death (Jiang et al. 2004). Mice expressing a knock-in mutation (IL-7R alpha Y449F) displayed defective homeostatic proliferation of naive CD4 and CD8 T-cells (Osbourne et al. 2007). The Y449 site is thus of particular interest because two critical IL-7 signaling pathways, the JAK/STAT pathway and the phosphatidylinositol 3-kinase (PI3K)/AKT pathway may originate from this site (Pallard et al. 1999).
The pre-pro-B cell growth-stimulating factor (PPBSF) is a self-assembling complex of IL7 and a variant beta-chain of hepatocyte growth factor (HGFbeta) (Lai & Goldschneider 2001). This 55 kDa heterodimer, unlike monomeric IL7, selectively stimulates proliferation and differentiation of pre-pro-B cells in a long-term bone marrow culture system and up-regulates IL7R alpha chain expression on pre-pro-B cell surface. It has been postulated that PPBSF is the active form of IL7 that normally induces IL7R-lo pre-pro-B cells to proliferate and differentiate into IL7R-hi pro-B cells, which then proliferate and differentiate into pre-B-cells on stimulation with monomeric IL7 (Wei et al. 2002).
IL-2 receptor gamma chain (IL2RG) associates with Janus Kinase 3 (JAK3). The carboxyl terminal region of IL2RG has been shown to be important for this asociation (Miyazaki et al. 1994, Zhu et al. 1998).
The IL7 receptor is a heterodimeric complex of the the common cytokine-receptor gamma chain (IL2RG, CD132, or Gc) and the IL7-receptor alpha chain (IL7RA, IL7R, CD127). Both chains are members of the type 1 cytokine family. Neither chain is unique to the IL7 receptor as IL7RA is utilized by the receptor for thymic stromal lymphopoietin (TSLP) while Gc is shared with the receptors for IL2, IL4, IL9, IL15 and IL21. Gc consists of a single transmembrane region and a 240aa extracellular region that includes a fibronectin type III (FNIII) domain thought to be involved in receptor complex formation. It is expressed on most lymphocyte populations. Null mutations of Gc in humans cause X-linked severe combined immunodeficiency (X-SCID), which has a phenotype of severely reduced T-cell and natural killer (NK) cell populations, but normal numbers of B cells. In addition to reduced T- and NK-cell numbers Gc knockout mice also have dramatically reduced B-cell populations suggesting that Gc is more critical for B-cell development in mice than in humans. Patients with severe combined immunodeficiency (SCID) phenotype due to IL7RA mutations (see Puel & Leonard 2000), or a partial deficiency of IL7RA (Roifman et al. 2000) have markedly reduced circulating T cells, but normal levels of peripheral blood B cells and NK cells, similar to the phenotype of Gc mutations, highlighting a requirement for IL7 in T cell lymphopoiesis. It has been suggested that IL7 is essential for murine, but not human B cell development, but recent studies indicate that IL7 is essential for human B cell production from adult bone marrow and that IL7-induced expansion of the progenitor B cell compartment is increasingly critical for human B cell production during later stages of development (Parrish et al. 2009).
IL7 has been shown to induce rapid and dose-dependent tyrosine phosphorylation of JAKs 1 and 3, and concomitantly tyrosine phosphorylation and DNA-binding activity of STAT5a/b (Foxwell et al. 1995). IL7RA was shown to directly induce the activation of JAKs and STATs by van der Plas et al. (1996). Jak1 and Jak3 knockout mice displayed severely impaired thymic development, further supporting their importance in IL7 signaling (Rodig et al. 1998, Nosaka et al. 1995).
The role of STAT5 in IL7 signaling has been studied largely in mouse models. Tyr449 in the cytoplasmic domain of IL7RA is required for T-cell development in vivo and activation of JAK/STAT5 and PI3k/Akt pathways (Jiang et al. 2004, Pallard et al. 1999). T-cells from an IL7RA Y449F knock-in mouse did not activate STAT5 (Osbourne et al. 2007), indicating that IL7 regulates STAT5 activity via this key tyrosine residue. STAT5 seems to enhance proliferation of multiple cell lineages in mouse models but it remains unclear whether STAT5 is required solely for survival signaling or also for the induction of proliferative activity (Kittipatarin & Khaled, 2007).
The model for IL7 receptor signaling is presumed to resemble that of other Gc family cytokines, based on detailed studies of the IL2 receptor, where IL2RB binds constitutively to JAK1 while JAK3 is pre-associated uniquely with the Gc chain. Extending this model to IL7 suggests a similar series of events: IL7RA constitutively associated with JAK1 binds IL7, the resulting trimer recruits Gc:JAK3, bringing JAK1 and JAK3 into proximity. The association of both chains of the IL7 receptor orients the cytoplasmic domains of the receptor chains so that their associated kinases (Janus and phosphatidylinositol 3-kinases) can phosphorylate sequence elements on the cytoplasmic domains (Jiang et al. 2005). JAKs have low intrinsic enzymatic activity, but after mutual phosphorylation acquire much higher activity, leading to phosphorylation of the critical Y449 site on IL7RA. This site binds STAT5 and possibly other signaling adapters, they in turn become phosphorylated by JAK1 and/or JAK3. Phosphorylated STATs translocate to the nucleus and trigger the transcriptional events of their target genes.
The role of the PI3K/AKT pathway in IL7 signaling is controversial. It is a potential T-cell survival pathway because in many cell types PI3K signaling regulates diverse cellular functions such as cell cycle progression, transcription, and metabolism. The ERK/MAPK pathway does not appear to be involved in IL7 signaling (Crawley et al. 1996).
It is not clear how IL7 influences cell proliferation. In the absence of a proliferative signal such as IL7 or IL3, dependent lymphocytes arrest in the G0/G1 phase of the cell cycle. To exit this phase, cells typically activate specific G1 Cyclin-dependent kinases/cyclins and down regulate cell cycle inhibitors such as Cyclin-dependent kinase inhibitor 1B (Cdkn1b or p27kip1). There is indirect evidence suggesting a possible role for IL7 stimulated activation of PI3K/AKT signaling, obtained from transformed cell lines and thymocytes, but not confirmed by observations using primary T-cells (Kittipatarin & Khaled, 2007). IL7 withdrawal results in G1/S cell cycle arrest and is correlated with loss of cdk2 activity (Geiselhart et al. 2001), both events which are known to be regulated by the dephosphorylating activity of Cdc25A. Expression of a p38 MAPK-resistant Cdc25A mutant in an IL-7-dependent T-cell line as well as in peripheral, primary T-cells was sufficient to sustain cell survival and promote cell cycling for several days in the absence of IL-7 (Khaled et al. 2005). Cdkn1b is a member of the CIP/KIP family of cyclin-dependent cell cycle inhibitors (CKIs) that negatively regulates the G1/S transition. In IL7 dependent T-cells, the expression of Cdkn1b was sufficient to cause G1 arrest in the presence of IL7. Withdrawal of IL7 induced the upregulation of Cdkn1b and arrested cells in G1 while siRNA knockout of Cdkn1b enhanced cell cycle progression. However, adoptive transfer of Cdkn1b-deficient lymphocytes into IL7 deficient mice indicated that loss of Cdkn1b could only partially compensate for the IL7 signal needed by T-cells to expand in a lymphopenic environment (Li et al. 2006), so though Cdkn1b may be involved in negative regulation of the cell cycle through an effect on cdk2 activity, its absence is not sufficient to fully induce cell cycling under lymphopenic conditions.
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1266695
Try the New WikiPathways
View approved pathways at the new wikipathways.org.Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
IL7RA JAK1 IL2RG
JAK3IL7RA
JAK1Annotated Interactions
IL7RA JAK1 IL2RG
JAK3IL7RA JAK1 IL2RG
JAK3IL7RA
JAK1The membrane-associated Gc chain interacts with the intermediate 1:1 IL7:IL7R complex, forming the active ternary complex, which binds IL7 with a 3-fold higher affinity (Kd =80 pM).
Tyr449 in the cytoplasmic domain of IL7RA is required for T-cell development in vivo and for activation of the JAK/STAT5 and PI3K/Akt pathways (Jiang et al. 2004, Pallard et al. 1999). Phosphorylated Tyr449 is believed to be a docking site for STAT5 and possibly PI3K, which are then activated by JAKs (Lin et al. 1995, Jiang et al. 2004). T-cells from an IL7RA Y449F knock-in mouse did not activate STAT5 (Osbourne et al. 2007), indicating that IL7 regulates STAT5 activity via this key tyrosine. It is thought that JAK1 phosphorylates IL7RA (Jiang et al. 2004).
In human thymocytes, IL7 activates STAT5. It is thought that phosphorylated Y449 in the cytoplasmic domain of the IL7RA is a docking site for STAT5 (Pallard et al. 1999). STAT5 can be activated in COS 7 cells when co transfected with JAK3 (Lin et al. 1996), though this does not demonstrate that JAK3 phosphorylates STAT5 proteins in response to IL7 in vivo (Lin & Leonard, 2000); it is not clear which JAK kinase phosphorylates STAT5 in vivo. T-cells from an IL7RA Y449F knock-in mouse did not activate STAT5 (Osbourne et al. 2007), indicating that Tyr449 is a key residue regulating IL7 mediated STAT5 activation. STAT3 is critical for early B cell differentiation, but the details of its involvement are unclear (Chou et al 2006).
Stimulation of human lymphocyte precursor cells with IL-7 induced tyrosine phosphorylation of the p85 subunit of PI3-kinase (PI3K) and activation of PI3K kinase activity (Dadi et al. 1994). It is thought that, depending on species differences and stage of lymphocyte development, IL7 induced PI3K pathway can promote signals that are important for survival and proliferation of both T cells and B cells.
Activation of PI3K leads to the generation of membrane associated PIP3 and membrane recruitment of AKT/PKB, the key downstream target of PI3K. AKT mediates phosphorylation of downstream substrates involved in regulation of cell survival and proliferation. IL7 induced activation of PI3K/AKT in human thymocytes has been reported (Pallard et al. 1999; Johnson et al. 2008). In mouse thymocytes IL7 stimulation resulted in the inactivation of BAD by serine phosphorylation; the PI3K/AKT pathway has been implicated in BAD phosphorylation. These results suggest that IL7 signaling via AKT inactivates the pro-apoptotic protein BAD promoting T cell survival (Li et al. 2004).
Rochman et al. (2009) suggest that IL7 promotes lymphocyte survival by activating the pro-survival PI3K/AKT signaling pathway and by increasing the expression of survival factors such as BCL2 and myeloid cell leukemia sequence 1 (MCL-1) while iinhibiting the expression of pro-apoptotic factors BAX and BAD.