An overview of IL-7 biology and its use in immunotherapy

Abstract

Interleukin (IL)-7 is required for T-cell development as well as for the survival and homeostasis of mature T-cells. In the thymus, the double negative (DN) CD4(-) CD8(-) thymocyte progenitor transition into double positive CD4+ CD8+ cells requires Notch and IL-7 signaling. Importantly, IL-7 seems to have a dose effect on T-cell development and, at high doses, DN progression is blocked. Naïve T-cells in the thymus, and after their exit to the periphery, are dependent on IL-7 and TCR signaling for survival. Upon antigen exposure, they proliferate and differentiate into memory T-cells. Because IL-7 intervenes at all stages of T-cell development and maintenance, it has been introduced recently into clinical trials as an immunotherapeutic agent for cancer patients (of particular note, those who had undergone T-cell depleting therapy) in an attempt to increase their population sizes of CD4+ and CD8+ cells overall, and specifically of CD8+ (CD45RA+)CCR7+ and/or CD27+), CD4+ (CD45RA+CD31+), and CD4+ central memory T-cells (CD45RA(-)CCR7+). Interestingly, IL-7 in humans induced a preferential expansion of naïve T-cells, resulting in a broader T-cell repertoire than before the treatment; this effect was independent of age. This suggests that IL-7 therapy could enhance immune responses in patients with limited naïve T-cell numbers as in aged patients or after disease-induced or iatrogenic T-cell depletion. This overview highlights the role of IL-7 on T-cells in mice and humans.

Figure 1. IL-7 Signaling

(A) IL-7 signaling is through the Jak-Stat pathway. IL-7 binds to its receptor composed of two chains: IL-7Rα and the γc chain. This induces the transphophorylation of Jak1 and Jak3 followed by the phosphorylation of the tyrosine Y449 on the IL-7Rα chain. Y449 becomes the docking site for Stat5. Stat5 becomes phosphorylated, dimerizes, and is translocated to the nucleus where it regulates gene expression implicated in differentiation. Socs-1 negatively regulates the responsiveness of T-cells to IL-7 by neutralizing the activity of Jaks. (B) Activation by IL-7 induces the phosphorylation on tyrosine residues of IL7Rα. PI3K is recruited to the membrane and binds to these tyrosine residues. PI3K becomes phosphorylated resulting in the phosphorylation of the phosphatidylinositol PIP2 into PIP3. PIP3 recruits signaling proteins with plekstrin domain (PH) to the membrane, such as PDK-1 and Akt. PIP3 in turned again into PIP2 by the phosphatase PTEN (phosphatase and tensin homolog on chromosome ten). Akt becomes active by phosphorylation and activates many downstream genes important for cell cycle and inhibition of apoptosis. After activation by Stat5 and Akt pathways through IL-7, and together with signaling through TCR, the synthesis of various proteins including Bcl-2 and Mcl-1 is initiated. These two proteins prevent mitochondrial death by blocking Bim and Bid from activating Bax and Bad.

Figure 2. Effect of IL-7 over-expression on T-cell development

Absolute counts from 6–12 week-old mice are shown. The * symbol corresponds to statistical significance. (A) Absolute thymocyte and DP counts are increased in the IL-7 transgenic mice with the lowest transgene expression and decreased in mice with the highest transgene expression. (B) Significant increase of TCRγδ, NK1.1, and B220 cells in IL-7 transgenic (Tg) mice at both high and low IL-7 over-expression.

Figure 3. rIL-7 therapy increases the absolute numbers of T-cell receptor excision circles (TRECs) in the peripheral blood

TREC numbers were measured in a total thirteen individual patients (◆) at 0, Day 7, Day 14, and Day 21 in CD4⁺ (left) and CD8⁺ cells and normalized per 10⁵ cells. Mean TREC numbers were calculated for cohorts that were treated with different doses of IL-7: ● 3 μg/kg; △ 10 μg/kg; □ 30 μg/kg; or, ○ 60 μg/kg. The decrease of TREC numbers at Day 7 is consistent with the decrease of naïve T-cells observed in these patients. TREC numbers were increased at Day 14 and Day 21.

Figure 4. Preferential increase of naïve and central memory CD4⁺ cells with rIL-7

A model of the relative representations of different CD4 subsets in the total T-cell pool from the three patients are shown before and after treatment with at 30 μg/kg of rIL-7. These model representations are intended primarily to convey concepts and as such are approximations of experimental data. The changes observed were independent of age. The blue color corresponds to naive CD4 cells, the red to central memory, the yellow to effector memory, and the green to effector RA cells.