IL-7 (interleukin-7) is a 25 kDa cytokine of the hemopoietin family that plays important roles in lymphocyte differentiation, proliferation, and survival (1-4). Human IL‑7 cDNA encodes 177 amino acids (aa) that include a 25 aa signal peptide (3). Human IL-7 shares approximately 60-63% aa sequence identity with mouse, rat, canine and feline IL-7, and 72-76% with equine, bovine, ovine, and porcine IL-7. Human and mouse IL-7 exhibit cross-species activity (2, 3).
IL-7 is produced by a wide variety of cells in primary and secondary lymphoid tissues, including stromal epithelial cells of the thymus, bone marrow, and intestines (1, 2, 5). Circulating IL-7 is limiting in healthy animals, but increases during lymphopenia (1, 6). IL-7 signals through a complex of the IL-7 Receptor alpha subunit (IL-7 R alpha , also known as CD127) with the common gamma chain ( gamma c) (1). The gamma c is also a subunit of the receptors for IL-2, -4, -9, -15, and -21 (1).
IL-7 R alpha is expressed on double negative (CD4-CD8-) and single positive (CD4+ or CD8+) naïve and memory T cells, but undergoes IL-7-mediated down‑regulation and shedding during antigen-driven T cell proliferation, and is absent on regulatory T cells (1, 2, 6-11). IL-7 contributes to the maintenance of all naïve and memory T cells, mainly by promoting expression of the anti-apoptotic protein Bcl-2 (9-11). It is required for optimal T cell-dendritic cell interaction (6). IL-7 is expressed early in B cell development prior to the appearance of surface IgM (1, 5, 9). In mouse, IL-7 activation of IL-7 R alpha is critical for both T cell and B cell lineage development, while in humans, it is required for T cell but not for B cell development (4, 9, 12, 13). However, IL-7 functions in both mouse and human pro-B cells to suppress premature Ig light chain recombination during proliferative growth (14, 15).
Like other common gamma-chain cytokines like IL-2 and IL-15,
IL-7 and its receptor, IL-7R, have been used in a variety of immunotherapy
applications, often in fluid tumors and in some instances of solid tumor models
(16). Sometimes use of recombinant IL-7 is preferential as current studies and
early clinical trials of cancer have found less severe toxicity or side effects
upon treatment with IL-7 in comparison to IL-15 or IL-2 (16).
In CAR-T cell therapies, enhanced expression and secretion
of human IL-7 and CCL19 have enhanced the ability of T cells to expand and
migrate in vitro
(17). Engineered CAR T cells expressing IL-7 or a
constitutively active IL-7R results in increased efficacy of CAR T anti-tumor
effects (16, 18). IL-7 is also frequently used in combination with IL-15 as a
supplement in cell culture of CAR T cells to support their expansion (19).
Additionally, IL-7/IL-15 in the presence of cord blood-derived T cells helps to
maintain their early differentiation state (20).
Monoclonal antibodies against IL-7R or small molecule
inhibitors against the IL-7R signaling pathway are commonly used in
circumstances of autoimmune diseases to delay disease progression (16). Also due to its ability to stimulate both
adaptive and innate immune cells, treatment with IL-7 has shown improved
survival in patients with sepsis who are at risk of deadly secondary infections
(21), providing evidence for IL-7 applications beyond cancer immunotherapy.
- Sasson, S.C. et al. (2006) Curr. Drug Targets 7:1571.
- Barata, J.T. et al. (2006) Exp. Hematol. 34:1133.
- Goodwin, R.G. et al. (1990) Proc. Natl. Acad. Sci. USA 86:302.
- Namen, A.E. et al. (1988) Nature 333:571.
- Shalapour, S. et al. (2012) PLoS ONE 7: e31939.
- Saini, M. et al. (2009) Blood 113:5793.
- Park, J.H. et al. (2004) Immunity 21:289.
- Vranjkovic, A. et al. (2007) Int. Immunol. 19:1329.
- Sudo, T. et al. (1993) Proc. Natl. Acad. Sci. 90:9125.
- Seddon, B. et al. (2003) Nat. Immunol. 4:680.
- Schluns, K.S. et al. (2000) Nat. Immunol. 5:426.
- Peschon, J.J. et al. (1994) J. Exp. Med. 180:1955.
- Pribyl, J.A. and T.W. LeBien (1996) Proc. Natl. Acad. Sci. 93:10348.
- Johnson, K. et al. (2012) J. Immunol. 188:6084.
- Nodland, S.E. et al. (2011) Blood 118:2116.
- Wang, C. et al. (2022) Int. J. Mol. Sci. 23(18).
N. et al. (2021) J Hematol Oncol. 14(118).
L. et al. (2022) Scientific Reports. 12(12506).
- Xu, Y. et al. (2014) Blood. 123(24):
- Marton, C. et al. (2022) Cancer
Gene Ther. 29(7).
- Winer, H. et al. (2022) Cytokine.