IL-12 instructs skin homing of human Th2 cells.
Distinct pattern of homing receptors determines the tissue preference for T cells to exert their effector functions. This homing competence is mostly determined early during T cell activation of naive T cells. In contrast, mechanisms governing the acquisition of particular homing receptors by T cells of the memory phenotype remain enigmatic. Th2 cell-mediated allergic diseases tend to flare during infections despite that these infections prime APCs to produce the prototypic Th1 cell-differentiating cytokine IL-12. In this study, we investigate the effect of IL-12 on the regulation of cutaneous lymphocyte Ag (CLA) on differentiated Th2 cells and consequences of this expression for allergic inflammation. Upon activation with IL-12, CLA- Th2 cells rapidly up-regulated IL-12Rbeta2 chain, alpha(1-3)-fucosyltransferase VII, and CLA molecules. IL-12-mediated CLA expression on Th2 cells was functional because it mediated rolling of these Th2 cells on E-selectin in vitro and migration into human skin grafts in SCID mice. CLA induction occurred immediately after exposure to IL-12 and was independent of IFN-gamma expression. In accordance, the transcription factor mediating IFN-gamma expression, T-bet, does not directly affect CLA expression. However, CLA expression was further enhanced after IL-12 treatment of T-bet+ -transfected Th2 cells in agreement with an increased IL-12 responsiveness of these cells caused by T-bet. The finding that IL-12 conferred skin-homing potential to already differentiated Th2 cells before inducing a switch in their cytokine production profile may explain the observed exacerbation of allergic skin diseases following bacterial infections.
Biedermann
Tilo
T
Novartis Institutes for Biomedical Research, Vienna, Austria.
Lametschwandtner
Günther
G
Tangemann
Kirsten
K
Kund
Julia
J
Hinteregger
Sonja
S
Carballido-Perrig
Nicole
N
Rot
Antal
A
Schwärzler
Christoph
C
Carballido
José M
JM
D000328:Adult; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm / Q000096:biosynthesis; D001424:Bacterial Infections / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology*; D002999:Clone Cells; D003876:Dermatitis, Atopic / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D005647:Fucosyltransferases / Q000096:biosynthesis; D006801:Humans; D018664:Interleukin-12 / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D016513:Mice, SCID; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis; D012867:Skin / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016038:Skin Transplantation / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; C063419:CTAGE1 protein, human; D008562:Membrane Glycoproteins; D016201:Receptors, Lymphocyte Homing; D018664:Interleukin-12; C502597:FUT7 protein, human; D005647:Fucosyltransferases