Interleukin-4 Regulates Eomesodermin In CD8⁺ T Cell Development and Differentiation

Cytokines regulate T cell development and function. Interleukin (IL)-4 is a cytokine classically associated with CD4⁺ T helper (T_H) differentiation, specifically T_H2 differentiation. However, IL-4 has recently been shown to drive the development of CD8⁺ innate-like lymphocytes (ILLs). CD8⁺ ILLs are non-conventional thymocytes that develop with characteristics typically associated with innate and/or memory immune cells, including surface expression of the activation/memory markers CD44 and CD122, expression of the T-box transcription factor Eomesodermin (Eomes) and the rapid production of interferon (IFN)-γ after ex vivo stimulation. Here we show that IL-4 is sufficient to promote Eomes expression in CD8 single-positive (SP) thymocytes in short-term in vitro culture and direct CD8+ ILL development in fetal thymic organ culture. Using genetic deficiency and pharmacologic inhibitors, we demonstrate that IL-4 up-regulation of Eomes in CD8SP thymocytes requires STAT6 and Akt signaling pathways. Next, we investigated the possibility that in addition to directing the fate of developing thymocytes, IL-4 might impact the function of mature CD8+ cells undergoing activation. We found that that in naïve peripheral CD8⁺ T the combination of IL-4 and low dose T cell receptor (TCR) stimulation is a potent inducer of Eomes. Futhermore, when combined, these stimuli promote the persistence of CD8⁺ T cells in an adoptive transfer model. Understanding how IL-4 directs CD8⁺ T cell differentiation may provide a novel way to enhance CD8+ T cell function in adoptive T cell therapies.