Full antagonist of the IL-7 receptor suppresses chronic inflammation in non-human primate models by controlling antigen-specific memory T cells

Abstract

Targeting the expansion of pathogenic memory immune cells is a promising therapeutic strategy to prevent chronic autoimmune attacks. Interleukin 7 (IL-7) is a limiting and potent cytokine produced by epithelial and stromal cells sustaining T-lymphocytes development, homeostasis and cell metabolism. Almost all conventional mature T lymphocytes express the IL-7 receptor (IL-7R), with the exception for naturally-occurring regulatory T-cells (Treg), constituting a rare opportunity to selectively strangle pathogenic effectors while preserving crucial natural regulators. In our recent study, we reported that therapeutic efficacy of antagonist anti- IL-7Rα mAbs in a non-human primate model of memory T cell-induced chronic inflammation depends on recognition of an epitope overlapping the IL-7 binding domain (site 1) and the receptor heterodimerization region (site-2b) (Nat Commun, 9(1):4483). We found that "site-1-only" mAbs prevented IL-7-induced JAK/STAT signaling but induced PI3K and Erk signaling and lacked efficacy in vivo, whereas "site-1 + 2b" mAbs were fully antagonist and demonstrated potent activity to control skin inflammation on the long term. The mechanism of action comprised the neutralization of IFN-γ producing antigen-specific memory T cells, without inducing lymphopenia or polyclonal T-cell functional or metabolic defects as generally observed previously in rodents.

Keywords: Chronic inflammation; IL-7; IL-7 receptor; memory T cells; monoclonal antibody.

Figure 1. FIGURE 1: Cytokine-induced receptor heterodimerization signaling mechanisms.

During the initiation step, IL-7 interacts with the extracellular domain 1 (D1) of IL-7Rα, generating the site-1 interface. This leads to the intermediate step where a 1:1 complex can associate with the shared common gamma-chain (γ_c) receptor. The binding of γ_c receptor involves an interface between IL-7 and γ_c called site-2a and an interface between D2 regions of the IL-7Rα and γ_c receptor called site-2b. The stabilized heterodimer complex activates the JAK/STAT and possible other signaling pathways.

Figure 2. FIGURE 2: Blockade of IL-7R selectively controls survival and expansion of stimulated antigen-specific memory T cells.

No antigenic stimulation: Interleukin-7 was described to control some degree of lymphocyte homeostasis (A); however blockade of IL7R in human and non-human primates does not modify the peripheral pool of T cells (B). Antigen restimulation: IL-7 is crucial to prevent apoptosis and sustain memory T cells proliferation after antigen restimulation (C). Full antagonistic anti-IL7R mAb blunts selectively antigen-specific memory T cells responses (D).