Structure

• Through the secretion of small soluble proteins, a cell can modify properties of its neighboring cells.  These factors, which include cytokines, lymphokines, and monokines, assist the immune system through a variety of essential pathways.  In order to identify such growth factors, cell cultures are assayed for the presence of proteins that stimulate lymphoid progenitors.  In 1988 Namen et al.cloned and sequenced a factor derived from a murine bone marrow stromal cell line, interleukin-7 (IL-7).  The following year the IL-7 human analog was isolated and sequenced.  Murine and human IL-7 share a 65% amino acid sequence identity, and exhibit cross-species reactivity (Goodwin et al.,1989).

• The receptor for IL-7 (IL-7R) belongs to the hematopoietin-receptor family.  This family of receptors is divided into three subgroups according to the use of the presence of an alpha, beta, or gamma chain at the binding site.  IL-7R shares a common gamma chain with the receptors for interleukin-4, -9, and -15 (Janeway et al., 1999).

Functions

• Interleukin-7 exerts pleiotropic effects on the immune system; it affects pre-B cells, thymocytes, mature T cells, lymphokine activated killer cells (LAK), monocytes, and macrophages. 

• Pre-B cells
• Both native and recombinant murine and human IL-7 stimulate the proliferation of pre-B cells harvested from bone marrow of either mice or humans.  IL-7 activates these cells in vitro in the absence of stromal cells (Namen et al.,1988; Goodwin et al., 1989). 
• Thymocytes
• If thymocytes are removed from their thymic microenvironment, then they fail to receive essential signals for their development.  Without these necessary growth factors, a T-cell receptorís V_beta genes are prevented from rearranging.  A bioassay, which examined the affect of many cytokines and other stimuli on fetal thymocyte suspensions, demonstrated that only IL-7 restores V(D)G rearrangement.  The recombination activating genes 1 and 2 may require the presence of IL-7 to maintain their expression (Muegge, 1993).
• Mature T-cells
• Originally, interleukin-2 (IL-2) was regarded as the main growth factor necessary for the proliferation of T-cells.  In combination with phorbol 12-myristate 13-acetate (PMA), IL-7 drives the activation of resting CD4+ and CD8+ T-cells along a pathway that is independent of IL-2 (Chazen et al.,1989). When naïve CD4+ T-cells are removed from their micro-enviroment, they quickly die.  IL-7 is present in secondary lymphoid tissue, a location that is part of naïve CD4+ T-cell circulation.  CD4+ T-cells bear the IL-7R on their cell surface.  IL-7 maintains naïve CD4+ T-cells in vitro for up to 15 days, which suggests that it is a survival factor for these cells (Webb et al., 1999).
• Lymphokine-Activated Killer (LAK) Cells
• In adoptive immunotherapy, a treatment for metastatic cancer, lymphocytes that possess anti-tumor activity are translocated into a patientís tumor (Rosenberg et al.,1986.)  In the presence of x-irradiated tumor cells, lymphocytes are activated against the antigens associated with the tumor.  The stimulation of anti-tumor lymphoid cells also occurs in the absence of tumor antigen.  Natural killer cells comprise more than 90% of these LAK cells.  A small portion, however, bears T-cell receptors, the cytolytic T lymphocytes (CTL) (Kuby et al., 2000).  High concentrations of IL-7 activate CD8+ T-cells in vitro to lyse fresh tumor cells, but to spare healthy cells (Alderson et al., 1990).  Jicha et al. provided the first demonstration of the activation of an antitumor CTL in vivo with IL-7 (1991).  IL-2 also can generate such cells in vivo, and these two cytokines work with equal potency.  When produced locally in murine tumor cells, IL-7 induces CD4+ T-cells to destroy the tumor.  Under similar circumstances, IL-2 activates CD8+ T-cells, suggesting that IL-7 utilizes a different pathway (Hock et al., 1991). 
• Monocytes and Macrophages
• Human peripheral blood monocytes are stimulated by human rIL-7 to secrete cytokines and lyse tumor cells.  Purified rIL-7 activates the release of interleukin-6, interleukin-1 alpha, interleukin-1 beta, and tumor necrosis factor-alpha from monocytes.  These cytokines perform central roles in the inflammatory process.  Secondly, monocytes and macrophages become cytotoxic for tumor cell lines after incubation with human rIL-7 (Alderson et al.,1991). 

• Normal maintenance and proliferation of thymic progenitor cells requires the presence of IL-7.  Mice deficient for IL-7 suffer from a 20-fold reduction in the number of double negative thymocytes.  This reduction significantly affects the number of gamma/delta T-cell receptors, while the amount of alpha/beta T-cell receptors lies near normal levels (Moore et al., 1996).

• Cyclosporine A (CsA), an immunosuppressive drug, inhibits the transcription of many lymphokines (for example,  IL-2 and IL-4), but does not affect IL-7.

Alderson MR, Sassenfeld HM, Widmer MB.  1990.  Interleukin 7 enhances cytolytic T lymphocyte generation and induces lymphokine-activated killer cells from human peripheral blood.  The Journal of Experimental Medicine 172: 577-587.

Alderson MR, Tough TW, Ziegler SF, Grabstein KH.  1991.  Interleukin 7 induces cytokine secretion and tumoricidal activity by human peripheral blood monocytes.  The Journal of Experimental Medicine 173: 923-930.

Chazen GD, Pereira GMB, LeGros G, Gillis S, Shevach EM.  1989.  Interleukin 7 is a T-cell growth factor.  Proceedings of the National Academy of Sciences, USA 86: 5923-5927.

Goodwin RG, Lupton S, Schmierer A, Hjerrild KJ, Jerzy R, Clevenger W, Gillis S, Cosman D, Namen AE.  1989.  Human interleukin 7: Molecular cloning and growth factor activity on human and murine B-lineage cells.  Proceedings of the National Academy of Sciences, USA 86: 302-306.

Hock H, Dorsch M, Diamanstein T, Blankenstein T.  1991.  Interleukin 7 induces CD4+ T cell-dependent tumor rejection.  The Journal of Experimental Medicine 174: 1291-1298.

Janeway CA, Travers P, Walport M, Capra JD.  1999.  Immunobiology: The immune system in health and disease.  New York, NY: Current Biology Publications.  p 291.

Jicha DL, Mule JJ, Rosenberg SA.  1991.  Interleukin 7 generates antitumor cytotoxic T lymphocytes against murine sarcomas with efficacy in cellular adoptive immunotherapy.  The Journal of Experimental Medicine  174: 1511-1515.

Kuby J, Kindt TJ, Osborne BA.  2000.  Immunology.  W.H. Freeman Company.  p 555-556.

Moore TA, von Freeden-Jeffry U, Murray R, Zlotnik A.  1996.  Inhibition of gammadelta T cell development and early thymocyte maturation in IL-7^-/- mice.  Journal of Immunology 157: 2366-2373.

Muegge K, Vila MP, Durum, SK.  1993.  Interleukin-7: A cofactor for V(D)J rearrangement of the T cell receptor ? gene.  Science 261: 93-95.

Namen AE, Schmierer AE, March CJ, Overell RW, Park LS, Urdal DL, Mochizuki DY.  1988.  B cell precursor growth-promoting factor: purification and characterization of a factor active on lymphocyte precursors.  The Journal of Experimental Medicine 167: 988-1002.

Rosenberg SA, Spiess P, Lafreniere R.  1986.  A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes.  Science 233: 1318-1321.

Webb LMC, Foxwell BMJ, Feldman M.  1999.  Putative role for interleukin-7 in the maintenance of the recirculating naïve CD4+ T-cell pool.  Immunology 98: 400-405.