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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.

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