Soluble CD25 imposes a low-zone IL-2 signaling environment that favors competitive outgrowth of antigen-experienced CD25high regulatory and memory T cells

Abstract

This study focused on soluble (s)CD25-mediated regulation of IL-2 signaling in murine and human CD4⁺ T cells. Recombinant sCD25 reversibly sequestered IL-2 to limit acute maximal proliferative responses while preserving IL-2 bioavailability to subsequently maintain low-zone IL-2 signaling during prolonged culture. By inhibiting IL-2 signaling during acute activation, sCD25 suppressed T-cell growth and inhibited IL-2-evoked transmembrane CD25 expression, thereby resulting in lower prevalence of CD25^high T cells. By inhibiting IL-2 signaling during quiescent IL-2-mediated growth, sCD25 competed with transmembrane CD25, IL2Rβγ, and IL2Rαβγ receptors for limited pools of IL-2 such that sCD25 exhibited strong or weak inhibitory efficacy in IL-2-stimulated cultures of CD25^low or CD25^high T cells, respectively. Preferential blocking of IL-2 signaling in CD25^low but not CD25^high T cells caused competitive enrichment of CD25^high memory/effector and regulatory FOXP3⁺ subsets. In conclusion, sCD25 modulates IL-2 bioavailability to limit CD25 expression during acute activation while enhancing CD25^highT-cell dominance during low-zone homeostatic IL-2-mediated expansion, thereby 'flattening' the inflammatory curve over time.

Keywords: CD25(high) T cells; Cell culture; Conventional T cells; FOXP3(+) regulatory T cells; Human and Mouse T cells; IL-2; IL2Rα; Soluble CD25 or sCD25; T cell activation; Transmembrane CD25.