The transcription factor KLF2 regulates T cell trafficking by promoting expression of the lipid-binding receptor S1P1 and the selectin CD62L. Recently, it was proposed that KLF2 also represses the expression of chemokine receptors. We confirmed the upregulation of the chemokine receptor CXCR3 on KLF2-deficient T cells. However, we showed that this was a cell-nonautonomous effect, as revealed by CXCR3 upregulation on wild-type bystander cells in mixed bone-marrow chimeras with KLF2-deficient cells. Furthermore, KLF2-deficient T cells overproduced IL-4, leading to the upregulation of CXCR3 through an IL-4-receptor- and eomesodermin-dependent pathway. Consistent with the increased IL-4 production, we found high concentrations of serum IgE in mice with T cell-specific KLF2 deficiency. Our findings support a model where KLF2 regulates T cell trafficking by direct regulation of S1P1 and CD62L and restrains spontaneous cytokine production in naive T cells.
Bibliographical noteFunding Information:
The authors wish to thank Caitlin Dejong for preparing and shipping Eomes-deficient bones and Thirumalai Ramalingam and Thomas Wynn for providing IL-13R-deficient bones. Jerry Lingrel provided Klf2 fl mice. Jason Cyster provided reagents and assistance with anti-S1P 1 staining. Xiao Jie Ding and Jason Vevea provided excellent technical support. We thank Oludare Odumade and Amy Moran for helpful discussion and critical review of the manuscript. The authors declare no competing financial interests. This research was supported by NIH grants R01-AI39560 (to K.A.H.), R01-AI38903 (to S.C.J.), and T32-AI007313 (to M.A.W.).