CXCL10 is required to maintain T-cell populations and to control parasite replication during chronic ocular toxoplasmosis.
OBJECTIVE
Toxoplasma gondii is a major cause of ocular disease, which can lead to permanent vision loss in humans. T cells are critically involved in parasite control, but little is known about the molecules that promote T-cell trafficking and migration in the retina. Thus, the aim of this study was to image and dissect the T-cell response during chronic toxoplasmic retinochoroiditis.


METHODS
C57BL/6 mice were infected with the Me49 strain of T. gondii, and T cells that infiltrated the eye were analyzed by flow cytometry and imaged using multiphoton microscopy. IFN-γ, CXCL9, CXCL10, and CXCR3 mRNA levels were measured by real-time PCR. To investigate the role of CXCL10, mice were treated with anti-CXCL10 antibodies, and histopathology and immunohistochemistry were performed to monitor changes in pathology, cellular infiltration, and parasite burden in the eye.


RESULTS
Infection with T. gondii leads to the infiltration of highly activated motile T cells into the eye. These cells express CXCR3 and are capable of producing IFN-γ and TNF-α, and CD8+ T cells express granzyme B. The expression of CXCL9 and CXCL10 in the retina was significantly upregulated during chronic infection. Treatment of chronically infected mice with anti-CXCL10 antibodies led to decreases in the numbers of CD3+, CD4+, and CD8+ T cells and the amount of IFN-γ mRNA expression in the retina and an increase in replicating parasites and ocular pathology.


CONCLUSIONS
The maintenance of the T-cell response and the control of T. gondii in the eye during chronic infection is dependent on CXCL10.
Norose
Kazumi
K
Department of Infection and Host Defense, Graduate School of Medicine, Chiba University, Chiba, Japan.
Kikumura
Akitoshi
A
Luster
Andrew D
AD
Hunter
Christopher A
CA
Harris
Tajie H
TH
D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D054357:Chemokine CXCL10 / Q000502:physiology*; D054370:Chemokine CXCL9 / Q000235:genetics; D002825:Chorioretinitis / Q000276:immunology / Q000469:parasitology*; D002908:Chronic Disease; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000235:genetics; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D036641:Microscopy, Fluorescence, Multiphoton; D012333:RNA, Messenger / Q000235:genetics; D054367:Receptors, CXCR3 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014122:Toxoplasma / Q000502:physiology*; D014126:Toxoplasmosis, Ocular / Q000276:immunology / Q000469:parasitology*
D057134:Antibodies, Neutralizing; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; C485433:Cxcl10 protein, mouse; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D007371:Interferon-gamma
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