Chemokine monokine induced by IFN-gamma/CXC chemokine ligand 9 stimulates T lymphocyte proliferation and effector cytokine production.
Monokine induced by IFN-gamma (MIG; CXC chemokine ligand (CXCL)9) is important in T lymphocyte recruitment in organ transplantation. However, it is not known whether this chemokine, in addition to its chemotactic properties, exerts any effect on T lymphocyte effector functions. For in vivo studies, we used a previously characterized murine model of chronic rejection. The recipient mice were treated with anti-MIG/CXCL9 Ab; graft-infiltrating cells were analyzed for IFN-gamma production. For in vitro studies, exogenous CXCR3 ligands were added to CD4 lymphocytes in MLRs, and the proliferative responses were measured. Separate experiments quantitated the number of IFN-gamma-producing cells in MLRs by ELISPOT. Neutralization of MIG/CXCL9, in the in vivo model, resulted in significant reduction in the percentage of IFN-gamma-producing graft-infiltrating T lymphocytes. In vitro experiments demonstrated that 1) exogenous MIG/CXCL9 stimulated CD4 lymphocyte proliferation in a MHC class II-mismatched MLR, 2) MIG/CXCL9 also increased the number of IFN-gamma-producing CD4 lymphocytes in ELISPOT, 3) neutralization of MIG/CXCL9 in MLR reduced T lymphocyte proliferation, 4) IFN-gamma-inducible protein 10/CXCL10 and IFN-inducible T cell alpha chemoattractant/CXCL11 had similar effects on T lymphocyte proliferation, 5) MIG/CXCL9 stimulated T lymphocyte proliferation in MHC class I- and total MHC-mismatched MLRs, 6) neutralization of CXCR3 reduced MIG/CXCL9-induced T lymphocyte proliferation and the number of IFN-gamma-positive spots on ELISPOT, and 7) the proliferative effects of MIG/CXCL9 were mediated via an IL-2-independent pathway and were controlled by IFN-gamma. This study demonstrates that MIG/CXCL9 stimulates T lymphocyte proliferation and effector cytokine production, in addition to its chemotactic effects. This novel observation expands our current understanding of MIG/CXCL9 biology beyond that of mediating T cell trafficking.
Whiting
David
D
Department of Surgery, Division of Cardiothoracic Surgery, David Geffen School of Medicine,University of California-Los Angeles, UCLA Medical Center, 10833 LeConte Avenue, Los Angeles, CA 90095, USA.
Hsieh
George
G
Yun
James J
JJ
Banerji
Anamika
A
Yao
William
W
Fishbein
Michael C
MC
Belperio
John
J
Strieter
Robert M
RM
Bonavida
Benjamin
B
Ardehali
Abbas
A
D000818:Animals; D054370:Chemokine CXCL9; D018925:Chemokines / Q000096:biosynthesis; D019743:Chemokines, CXC / Q000502:physiology*; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005786:Gene Expression Regulation; D006084:Graft Rejection; D016027:Heart Transplantation / Q000276:immunology; D006648:Histocompatibility; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D015846:Monokines / Q000096:biosynthesis*; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D054370:Chemokine CXCL9; D018925:Chemokines; D019743:Chemokines, CXC; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D016207:Cytokines; D015846:Monokines; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D007371:Interferon-gamma