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).
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.
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).
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 Vbeta
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).
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.,
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:
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.