CXCR3 ligands contribute to Th1-induced inflammation but not to homing of Th1 cells into the lung.
Th1 cells are implicated in numerous pulmonary inflammatory disorders, and adoptive transfer of alloreactive Th1 cells mediates lung injury and inflammation in mice. In response to Th1-mediated immune injury, CXCR3 ligands IP10 and MIG are markedly induced. Because Th1 cells express high levels of CXCR3, their recruitment and activity may be influenced by CXCR3 ligands. To examine the role of CXCR3 ligands, the authors inhibited CXCR3-ligand interaction by 2 approaches: (1) antibody ablation of CXCR3 ligands IP10 (CXCL10/interferon-gamma -inducible 10-kDa protein) and MIG (CXCL9/monokine-induced by interferon-gamma), and (2) use of cxcr3(-/-) mice. Antibody neutralization of IP10 and MIG reduced Th1-cell mediated lung inflammation but did not alter Th1-cell influx in the lung. In contrast, a lack of CXCR3 on host cells had no effect on Th1 cells influx or acute inflammation. In vitro, ablation of endogenous IP10 and MIG inhibited antigen-mediated Th1-cell proliferation. These results suggest that the influx of alloreactive Th1 cells into the lung does not require CXCR3 ligands, but that these chemokines do affect Th1-cell proliferation and activity within the affected tissue. Other CXCR3(+) leukocytes do not contribute to acute alloimmune injury.
Manicone
Anne M
AM
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, and Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. manicone@u.washington.edu
Burkhart
Kristi M
KM
Lu
Bao
B
Clark
Joan G
JG
D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies; D049109:Cell Proliferation; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000276:immunology / Q000378:metabolism*; D054370:Chemokine CXCL9 / Q000276:immunology / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D008024:Ligands; D008168:Lung / Q000276:immunology* / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000276:immunology* / Q000473:pathology; D054367:Receptors, CXCR3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D013997:Time Factors
D000906:Antibodies; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; C485433:Cxcl10 protein, mouse; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D008024:Ligands; D054367:Receptors, CXCR3; D011994:Recombinant Proteins