The Ikaros zinc finger transcription factor Aiolos as a novel regulator of T cell migration

Abstract Chemokine signaling is an integral component of lymphocyte migration, activation, and survival. The chemokine receptor CXCR3 is highly expressed on CD4+ T helper 1 (TH1) cells, which play a critical role in the adaptive immune response against intracellular pathogens. While CXCR3 helps direct TH1 cells to sites of inflammation or infection, it has also been implicated in a multitude of autoimmune diseases and cancers. Thus, understanding the molecular mechanisms that regulate CD4+ T cell migration is imperative for preventing immunopathology. Here, we identify the Ikaros zinc finger (IkZF) transcription factor Aiolos (IkZF3) as a positive regulator of CXCR3 expression in CD4+ T cells in a murine influenza model. Initially, we show decreased numbers of Aiolos-deficient antigen-specific CD4+ T cells in the lung, which correlates with decreased CXCR3 expression. RNA-seq and ATAC-seq analyses of in vitro-generated WT and Ikzf3−/− TH1 cells revealed decreased Cxcr3 transcript and reduced chromatin accessibility at regulatory regions of Cxcr3 in the absence of Aiolos, respectively. Collectively, these data imply a novel role for Aiolos in positively regulating CXCR3 expression in TH1 cells. Given these findings, we seek to define the functional effects of Aiolos deficiency on T cell migration and the molecular mechanism(s) by which Aiolos directly and/or indirectly regulates migration. Future work is aimed at determining whether Aiolos affects CXCR3 expression through direct association or indirectly via impacts on other factors. K. J. O. is supported by a grant from The National Institutes of Health (NIH) AI134972, as well as from The Ohio State University College of Medicine and The Ohio State University Comprehensive Cancer Center.