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

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 CD25high T cells. By inhibiting IL-2 signaling during quiescent IL-2-mediated growth, sCD25 competed with transmembrane CD25, IL2R beta gamma, and IL2R alpha beta gamma receptors for limited pools of IL-2 such that sCD25 exhibited strong or weak inhibitory efficacy in IL-2-stimulated cultures of CD25low or CD25high T cells, respectively. Preferential blocking of IL-2 signaling in CD25low but not CD25high T cells caused competitive enrichment of CD25high memory/effector and regulatory FOXP3+ subsets. In conclusion, sCD25 modulates IL-2 bioavailability to limit CD25 expression during acute activation while enhancing CD25high T-cell dominance during low-zone homeostatic IL-2-mediated expansion, thereby 'flattening' the inflammatory curve over time.

Automated summary

This study investigates the regulation of IL-2 signaling in CD4+ T cells by soluble CD25 (sCD25). The results show that sCD25 reversibly sequesters IL-2, limiting acute proliferative responses but maintaining IL-2 availability for prolonged culture. sCD25 inhibits T-cell growth and CD25 expression, resulting in a lower prevalence of CD25high T cells. Additionally, sCD25 competes with CD25 and IL-2 receptors for limited pools of IL-2, leading to preferential enrichment of CD25high memory/effector and regulatory FOXP3+ subsets.