Interleukin-7 signaling

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Homo sapiens
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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 (IL7R, IL7RA, CD127). Both chains are members of the type 1 cytokine family. Neither chain is unique to the IL7 receptor as IL7R is utilized by the receptor for thymic stromal lymphopoietin (TSLP) while IL2RG is shared with the receptors for IL2, IL4, IL9, IL15 and IL21. IL2RG 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 IL2RG 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, Il2rg knockout mice also have dramatically reduced B-cell populations suggesting that Il2rg is more critical for B-cell development in mice than in humans. Patients with severe combined immunodeficiency (SCID) phenotype due to IL7R mutations (see Puel & Leonard 2000), or a partial deficiency of IL7R (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 IL2RG 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). IL7R 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 IL7R 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 believed 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 IL2RG chain. Extending this model to IL7 suggests a similar series of events: IL7R constitutively associated with JAK1 binds IL7, the resulting trimer recruits IL2RG: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 IL7R. 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 IL7 (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.
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