An essential role for the IL-2 receptor in Treg cell function

Abstract

Regulatory T (Treg) cells, expressing abundant amounts of the IL-2 receptor (IL-2R), are reliant on IL-2 produced by activated T cells. This feature implied a key role for a simple network based on IL-2 consumption by Treg cells in their suppressor function. However, congenital deficiency in IL-2R results in reduced expression of the Treg cell lineage specification factor Foxp3, confounding experimental efforts to understand the role of IL-2R expression and signaling in Treg suppressor function. Using genetic gain and loss of function approaches, we demonstrate that IL-2 capture is dispensable for control of CD4+ T cells, but is important for limiting CD8+ T cell activation, and that IL-2R dependent STAT5 transcription factor activation plays an essential role in Treg cell suppressor function separable from T cell receptor signaling.

An increased CD25-positive intestinal regulatory T lymphocyte population is dependent upon Cox-2 activity in the Apcmin/+ model

“…The observation that constitutive STAT-5b activation increased intestinal adenoma size in the Apc Min/1 mouse is consistent with a role for IL-2R--STAT-5 T reg activation in promoting intestinal tumorigenesis [29]. It is noteworthy that constitutive STAT-5b activation abrogated proinflammatory cytokine secretion while modifying expression of cell surface molecules by T lymphocytes [29]. These, taken together, suggest that abrogation of an increased intestinal CD25…”

“…Additionally, the Ikaros transcription factor Helios is known to have STAT-5b as one of its principal targets in mice, stabilizing STAT-5-dependent IL-2 responsiveness [21]. The observation that constitutive STAT-5b activation increased intestinal adenoma size in the Apc Min/1 mouse is consistent with a role for IL-2R--STAT-5 T reg activation in promoting intestinal tumorigenesis [29]. It is noteworthy that constitutive STAT-5b activation abrogated proinflammatory cytokine secretion while modifying expression of cell surface molecules by T lymphocytes [29].…”

Mechanistic approaches for the prevention and treatment of chronic GVHD

“…However, at low physiologic concentrations, IL-2 is a critical homeostatic cytokine that is required for normal Treg development, expansion, activity, and survival. [89][90][91] In a phase 1 clinical trial, daily administration of IL-2 at a dose of 1 3 10 6 IU/m 2 per day was demonstrated to be safe and well tolerated in patients with steroid-refractory chronic GVHD. Notably, daily IL-2 treatment at this low dose selectively enhanced CD4…”

Differential Roles of IL-2 Signaling in Developing versus Mature Tregs

“…While it is generally assumed that continued IL-2 signaling is needed for Treg survival, suppressor function, and lineage maintenance, these inferences have largely been extrapolated from germline knockout models, blocking antibody experiments, and in vitro studies. The roles of continued IL-2 signaling following Treg development, and the signals by which IL-2 executes these roles, remain imperfectly understood (Chinen et al, 2016). …”