Intracellular Signaling Networks in the Immune Response: Pathways Activated by Interleukin-2 and Interleukin-4 Receptors and their Roles in T Cell Proliferation

Abstract

Cells sense and respond to chemical and physical stimuli through signal transduction pathways, which mediate cell proliferation, differentiation, migration, and survival. The cytokines interleukin-2 (IL-2) and interleukin-4 (IL-4) are key regulators of the adaptive immune system, particularly influencing the clonal expansion and differentiation of T cells. At least in culture, both synergistic and antagonistic effects of IL-2 and -4 co-stimulation have been reported; the antagonism, when observed, is thought to arise from the utilization of a common subunit shared by IL-2 and IL-4 receptors. We have sought to characterize IL-2 and IL-4 signaling at the level of intracellular pathways activated by these receptors. IL-2 receptors are known to activate the Ras/extracellular signal-regulated kinase (Erk) and phosphoinositide (PI) 3-kinase pathways as well as the STAT5 transcription factor. IL-4 is unique among cytokines in that it does not activate Ras⁄Erk; it does activate PI 3-kinase⁄Akt as well as a distinct STAT, STAT6.

The HT-2 mouse T cell line responds to both IL-2 and -4. We found that IL-4 initially antagonizes, and later synergizes with, IL-2-stimulated HT-2 cell proliferation in a dose-dependent manner. IL-4 also stimulates cell adhesion in static cultures. At the level of intracellular signaling, IL-4 antagonizes IL-2-stimulated activation of Akt, possibly through competition for limiting amounts of common receptor subunit and/or PI 3-kinase. Because IL-4 alone does not promote any Erk activation, we were surprised to find that IL-4 enhances IL-2-stimulated activation of Erk. IL-2⁄IL-4 co-stimulation provokes transient activation of STAT5 and prolonged activation of STAT6. This extended STAT6 activation may be critical in the IL-2⁄IL-4 induced synergy in T cell growth. Currently, we are investigating the crosstalk between these pathways and their functional roles in IL-2 and IL-4-stimulated T cell responses.