KLF2 transcription-factor deficiency in T cells results in unrestrained cytokine production and upregulation of bystander chemokine receptors.
The transcription factor KLF2 regulates T cell trafficking by promoting expression of the lipid-binding receptor S1P(1) 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 S1P(1) and CD62L and restrains spontaneous cytokine production in naive T cells.
Weinreich
Michael A
MA
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Takada
Kensuke
K
Skon
Cara
C
Reiner
Steven L
SL
Jameson
Stephen C
SC
Hogquist
Kristin A
KA
D000818:Animals; D007073:Immunoglobulin E / Q000097:blood; D015847:Interleukin-4 / Q000096:biosynthesis*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019041:L-Selectin / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054367:Receptors, CXCR3 / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
C515188:Cxcr3 protein, mouse; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D054367:Receptors, CXCR3; D049349:Receptors, Lysosphingolipid; D020825:T-Box Domain Proteins; D019041:L-Selectin; D015847:Interleukin-4; D007073:Immunoglobulin E