STAT1 in peripheral tissue differentially regulates homing of antigen-specific Th1 and Th2 cells.
Th1 and Th2 effector CD4+ T cells orchestrate distinct counterregulatory biological responses. To deliver effective tissue Th1- and Th2-type responses, Th1 and Th2 cell recruitment into tissue must be differentially regulated. We show that tissue-derived STAT1 controls the trafficking of adoptively transferred, Ag-specific, wild-type Th1 cells into the lung. Trafficking of Th1 and Th2 cells is differentially regulated as STAT6, which regulates Th2 cell trafficking, had no effect on the trafficking of Th1 cells and STAT1 deficiency did not alter Th2 cell trafficking. We demonstrate that STAT1 control of Th1 cell trafficking is not mediated through T-bet. STAT1 controls the recruitment of Th1 cells through the induction of CXCL9, CXCL10, CXCL11, and CXCL16, whose expression levels in the lung were markedly decreased in STAT1-/- mice. CXCL10 replacement partially restored Th1 cell trafficking in STAT1-deficient mice in vivo, and deficiency in CXCR3, the receptor for CXCL9, CXCL10, and CXCL11, impaired the trafficking of adoptively transferred Th1 cells in wild-type mice. Our work identifies that STAT1 in peripheral tissue regulates the homing of Ag-specific Th1 cells through the induction of a distinct subset of chemokines and establishes that Th1 and Th2 cell trafficking is differentially controlled in vivo by STAT1 and STAT6, respectively.
Mikhak
Zamaneh
Z
Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Fleming
Carolyn M
CM
Medoff
Benjamin D
BD
Thomas
Seddon Y
SY
Tager
Andrew M
AM
Campanella
Gabriele S
GS
Luster
Andrew D
AD
D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051116:Receptors, Scavenger / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*
D000941:Antigens; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C485433:Cxcl10 protein, mouse; C515203:Cxcl11 protein, mouse; C498926:Cxcl16 protein, mouse; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D051116:Receptors, Scavenger; D050794:STAT1 Transcription Factor; D050800:STAT6 Transcription Factor; C494080:Stat1 protein, mouse; C494100:Stat6 protein, mouse; D010047:Ovalbumin