Smad signaling determines the fate of activated CTLs via multiple intersecting signaling pathways

Abstract

Abstract Immune responses to an infection are controlled by various factors including antigens, co-stimulatory molecules and cytokines present in the tissue micro-environment. These factors modulate the differentiation of effector CD8 T cells and memory subsets. TGFβ plays a pivotal role in fate determination of activated CTLs. In TGFβ pathway, Smad proteins are critical for downstream signaling. Using transgenic animal models and pharmacological inhibitors, we investigate the role of TGFβ and Smad proteins in fate determination of activated CTLs. We identified that TGFβ and Smad proteins play important roles in regulating the expression of several homing receptors on effector CD8 T cells (KLRG1) and memory subsets (CD62L, S1PR1 and CD103). In addition, targeted-ablation of different Smad proteins alter the expression levels of different transcription factors that participate in fate determination, including Eomes and KLF2. We found that while Smad proteins regulate the gene expression in canonical TGFβ pathway, they also have TGFβ independent functions in determining the fate of activated CTLs. Particularly, we show that Smad4 is required for the expression of KLRG1 and acts as a suppressor of CD103, independent of TGFβ. This study reveals a novel role for Smad signaling cascade in guiding the fate decisions of activated CTLs and tissue localization via multiple intersecting signaling pathways.