Receptor for IL7

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Structure

Interleukin-7 can act on various cells through its receptor IL-7R. IL-7R is a heterodimer that consists of an a chain (CD 127) that specifically binds IL-7 and the common g chain gc (CD132), which is also a component of several other cytokine receptors: IL-2, IL-4, IL-9, IL-15, and IL-21. Interleukin-7 receptor is a member of the hematopoietin/cytokine receptor superfamily; both IL-7Ra and gc have a pair of conserved extracellular cysteine residues and an extracellular Trp-Ser-X-Trp-Ser motif and lack intrinsic tyrosine kinase activity (Figure 1). The a chain of IL-7R can also bind thymic stromal-derived lymphopoi-etin (TSLP), a cytokine that is important in early stages of B- and T-cell development. IL-7Ra is a type 1 membrane glycoprotein. It has a 220-amino acid extracellular domain, a 25-amino acid transmembrane fragment, and a 195-amino acid cytoplasmic tail. The mature protein has an observed molecular weight of about 75 kDa, although the predicted molecular weight is 49.5 kDa; the difference is probably caused by post-translational modification of one or more of

Signal Transduction

Interleukin 7 can signal through several nonreceptor tyrosine kinases associated with the cytoplasmic tail of the receptor. This includes the JAK/STAT pathway, Src family kinases (p59fyn in mice and p59fyn and p53/p56lyn in humans), and PI-3 kinase. In T lymphocytes, the MAPK family (p38) is also involved. IL-7 activates JAK1 and JAK3 kinases, which are also activated by the cytokines that share the gc receptor subunit. JAK kinases can further activate signal transducers and activators of transcription (STAT1, STAT3, and STAT5), which in turn translocate to the nucleus and activate DNA transcription. It has been demonstrated that stimulation of the pro-T cells by IL-7 results in clathrin phosphorylation. Because clathrin is involved in internalization of many receptors, its phosphorylation by IL-7 may affect the internalization of the IL-7 receptor. The disorder in JAK-mediated signal transduction is a cause for the immunodeficiency syndrome severe combined immunodeficiency (SCID). The mutation in the JAK3 kinase gene as well as in the a chain gene of the IL-7 receptor results in autosomal, recessive SCID, whereas mutation in the gc chain gene causes X-linked SCID (SCID-X).

Il7ra Gene

Figure 1 The Schematic Structure of IL-7R. The receptor for IL-7 consists of a specific a chain and a common gc chain. The IL-7Ra is also a part of thymic stromal lymphopoietin (TSLP), whereas the gc chain is present in other cytokines such as IL-2, IL-4, IL-9, IL-15, and IL-21. The cellular signaling upon binding of IL-7 to IL-7R can be mediated by the JAK/STAT pathway, PI-3 kinase, or Src kinases family. Reprinted from "Biological and clinical implications of interleukin-7 and lymphopoiesis" by P. M. Appasamy from Cytokines, Cellular & Molecular Therapy, www.tandf.no/ccmt, 1999, 5, 25-39, by permission of Taylor & Francis AS.

Figure 1 The Schematic Structure of IL-7R. The receptor for IL-7 consists of a specific a chain and a common gc chain. The IL-7Ra is also a part of thymic stromal lymphopoietin (TSLP), whereas the gc chain is present in other cytokines such as IL-2, IL-4, IL-9, IL-15, and IL-21. The cellular signaling upon binding of IL-7 to IL-7R can be mediated by the JAK/STAT pathway, PI-3 kinase, or Src kinases family. Reprinted from "Biological and clinical implications of interleukin-7 and lymphopoiesis" by P. M. Appasamy from Cytokines, Cellular & Molecular Therapy, www.tandf.no/ccmt, 1999, 5, 25-39, by permission of Taylor & Francis AS.

Other details describing the structure of IL-7R and IL-7 signaling have been reviewed elsewhere [1-3].

IL-7R Distribution

The presence of IL-7R was reported mainly in hematopoietic human and murine cell systems and selected myeloid cells. The IL-7Ra chain is present on bone marrow progenitor cells, lymphoid T and B precursors, and on most mature T cells. Recently, its presence on epithelial cells and neurons, as well as on human microvascular endothelial cells and some tumors, was reported.

After IL-7 binding, IL-7R transduces several biological signals, playing an important role in the function of the immune system. The cytokine, via its receptor, supports the maturation and augment proliferation of pre-B and pre-T cells. Murine B lymphocyte development is critically dependent on IL-7 availability. The interleukin-7 receptor is essential for Peyer's patches (PP) development. Lymphoid organ-specific mesenchymal tissue that possesses IL-7R is involved in the initial phase of PP formation. Accumulating evidence indicates that both PP and lymph nodes (LN) originate from a common precursor, characterized by the presence of IL-7R. The precursor differentiation into LN or PP, and their further functional properties, are controlled by the local environment.

The Presence of IL-7R on Endothelial Cells

The endothelium is a type of highly specialized, structurally and functionally heterogenous mesodermal-derived epithelium. Microvascular endothelium controls the body compartmentation and homing of lymphocytes into lymphoid as well as nonlymphoid sites, in a tissue-specific manner. Selectins (E- and P-) and other endothelium-specific adhesive molecules called addressins (ligands for selectins) initiate the process of leukocytes' adhesion to the vascular wall. Under the chemoattractive influence of endothelium-presented chemokines, activated leukocytes adhere firmly and finally transmigrate through the vascular wall to the surrounding tissues. Endothelial cells play fundamental roles not only in normal processes such as wound healing but also in pathological ones such as atherosclerosis, inflammation, and cancer progression and metastasis.

In 1993 it was shown that murine endothelial cells from peripheral lymph nodes could be specifically activated by IL-7. In cells grown in the presence of IL-7, expression of lectin adhesion molecule and a selective induction of addressin (MECA 79 antigen) expression were noticed. These observations strongly suggested the presence of IL-7R on murine endothelial cells. Further study revealed that human endothelial cells possess the receptor for IL-7. The a chain of the receptor (IL-7R) was detected in five endothe-lial cell lines, derived from peripheral or mesenteric lymph nodes, lung, and appendix.

It has been postulated that there is a close association of the hematopoietic and endothelial developmental lineages because they both arise from a common precursor, the hemangioblast. Hence, the fact of the presence of an IL-7 receptor on hematopoietic as well as on endothelial cells may support this hypothesis.

Activity of IL-7 on endothelial cells is achieved through activation of its specific receptor, resulting in induction of adhesion molecules and/or cytokines. It could be hypothesized that IL-7, activating endothelial cells, may act indirectly, inducing the production of another growth factor such as VEGF or bFGF; however, no evidence supports this hypothesis. It has also been shown that IL-7 can induce signal transduction events in cells that do not express IL-7R because of the ability to involve other surface receptors such as FLT3 and c-kit.

IL-7R in Cancer

Because IL-7 is a known lymphocyte growth and differentiation factor, it also participates in the development of several hematological malignancies. However, the IL-7 receptor mRNA has also been detected in many nonhemato-logical tumor in vitro cell lines. IL-7 was found to be a potent growth factor for breast cancer cells. Breast cancer cell lines, cancer tissue biopsies, and normal breast tissue express IL-7R mRNA. Moreover, the expression of IL-7R and its signaling molecules is higher in tumor tissue of patients with a poor clinical outcome. The aberrant expression of IL-7, IL-7R, and their signaling complex may influence the proliferation of breast cancer cells and disease progression, supporting lymphangiogenesis of the solid tumors.

References

1. Appasamy, P. M. (1999). Biological and clinical implications of inter-leukin-7 and lymphopoiesis. Cytokines. Cell. Mol. Ther. 5, 25-39. An extensive review about IL-7 and IL-7R, their biological functions, and potential clinical applications of IL-7.

2. Hofmeister, R., Khaled, A. R., Benbernou, N., Rajnavolgyi, E., Muegge, K., and Durum, S. K. (1999). Interleukin-7: Physiological roles and mechanisms of action. Cytokine Growth Factor Rev 10, 41-60. This publication is a very good review describing two main aspects of the biological activity of IL-7 toward lymphoid cells: the trophic effect and an effect supporting V(D)J recombination.

3. Fry, T. J., and Mackall, C. L. (2002). Interleukin-7: From bench to clinic. Blood 99, 3892-3904. An excellent review focused on biological activity of IL-7 from medical and clinical point of view.

Further Reading

Al-Rawi, M. A. A., Rmali, K., Watkins, G., Mansel, R. E., and Jiang, W. G. (2004). Aberrant expression of interleukin-7 (IL-7) and its signalling complex in human breast cancer. Eur. J. Cancer 40, 494-502.

Bizouarne, N., Denis, V., Legrand, A., Monsigny, M., and Kieda, C. (1993). A SV-40 immortalized murine endothelial cell line from peripheral lymph node high endothelium expresses a new alpha-L-fucose binding protein. Biol. Cell. 79, 209-218.

Denis, V., Dupuis, P., Bizouarne, N., de O. Sampaio, S., Hong, L., Lebret, M., Monsigny, M., Nakache, M., and Kieda, C. (1996). Selective induction of peripheral and mucosal endothelial cell addressins with peripheral lymph nodes and Peyer's patch cell-conditioned media. J. Leukocyte Biol. 60, 744-752.

Dus, D., Krawczenko, A., Zalecki, P., Paprocka, M., Wiedlocha, A., Goupille, C., and Kieda, C. (2003). IL-7 receptor is present on human microvascular endothelial cells. Immunol Lett. 86, 163-168. This paper describes for the first time the presence of IL-7R on human microvas-cular endothelial cells.

Goodwin, R. G., Friend, D., Ziegler, S. F., Jerzy, R., Falk, B. A., Gimpel, S., Cosman, D., Dower, S. K., March, C. J., and Namen, A. E. (1990).

Cloning of the human and murine interleukin-7 receptors: Demonstration of a soluble form and homology to a new receptor superfamily. Cell 60, 941-951.

Kieda, C., Paprocka, M., Krawczenko, A., Zalecki, P., Dupuis, P., Monsigny, M., Radzikowski, C., and Dus, D. (2002). New human microvascular endothelial cell lines with specific adhesion molecules phenotypes. Endothelium 9, 247-261.

Yoshida, H., Naito, A., Inoue, J-I., Satoh, M., Santee-Cooper, S. M., Ware, C. F., Togawa, A., Nishikawa, S., and Nishikawa, S-I. (2002). Different cytokines induce surface lymphotoxin-aß on IL-7 receptor-a cells that differentially engender lymph nodes and Peyer's patches. Immunity 17, 823-833.

Capsule Biographies

Danuta Dus, Ph.D. hab., is a head of Laboratory of Cellular Interactions at the Institute of Immunology and Experimental Therapy at the Polish Academy of Sciences in Wroclaw, Poland; Agnieszka Krawczenko, Ph.D., is an assistant professor at the Laboratory of Cellular Interactions. The scientific activity of the laboratory concerns predictive markers of metastasis. The aims of the study are molecular mechanisms engaged in the process of mutual interactions of tumor cells with endothelial cells at the site of tumor cell extravasation, which determine the organ specificity of metastatic secondary growth. The work is supported by the Ministry of Scientific Research and Information Technology, The State Committee for Scientific Research (KBN), and by The Foundation for Polish Science (FNP).

Claudine Kieda, Ph.D., is heading the Cell Recognition: Endogenous Lectins team in the Centre for Molecular Biophysics in Orléans, France. The laboratory is focusing on molecular mechanisms of cellular interaction between endothelium and circulating cells leading to invasion. She first discovered endogenous lectins in lymphocytes; her actual special interests are glycoconjugates and their receptors as key recognition signals in inflammation and metastasis. She was awarded the CNRS bronze medal, and her work is supported by ARC, CNRS, and private foundations such as Jérôme Lejeune.

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