CXCR3-Dependent CD4+ T Cells Are Required to Activate Inflammatory Monocytes for Defense against Intestinal Infection

PLoS Pathogens

Charlotte E. Egan¹  Kirk J. Maurer²  Sara B. Cohen³  Steve Oghumu³  Abhay R. Satoskar⁴  Eric Y. Denkers⁴ 

[1] Center for Animal Resources and Education, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America;Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America;Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America;Department of Pathology, The Ohio State University Medical Center, Columbus, Ohio, United States of America

关键词: T cells;    Inflammation;    Gastrointestinal tract;    Monocytes;    Parasitic intestinal diseases;    Toxoplasma gondii;    Small intestine;    Toxoplasma;   

DOI  :  10.1371/journal.ppat.1003706

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Chemokines and their receptors play a critical role in orchestrating immunity to microbial pathogens, including the orally acquired Th1-inducing protozoan parasite Toxoplasma gondii. Chemokine receptor CXCR3 is associated with Th1 responses, and here we use bicistronic CXCR3-eGFP knock-in reporter mice to demonstrate upregulation of this chemokine receptor on CD4+ and CD8+ T lymphocytes during Toxoplasma infection. We show a critical role for CXCR3 in resistance to the parasite in the intestinal mucosa. Absence of the receptor in Cxcr3−/− mice resulted in selective loss of ability to control T. gondii specifically in the lamina propria compartment. CD4+ T cells were impaired both in their recruitment to the intestinal lamina propria and in their ability to secrete IFN-γ upon stimulation. Local recruitment of CD11b+Ly6C/G+ inflammatory monocytes, recently reported to be major anti-Toxoplasma effectors in the intestine, was not impacted by loss of CXCR3. However, inflammatory monocyte activation status, as measured by dual production of TNF-α and IL-12, was severely impaired in Cxcr3−/− mice. Strikingly, adoptive transfer of wild-type but not Ifnγ−/− CD4+ T lymphocytes into Cxcr3−/− animals prior to infection corrected the defect in inflammatory macrophage activation, simultaneously reversing the susceptibility phenotype of the knockout animals. Our results establish a central role for CXCR3 in coordinating innate and adaptive immunity, ensuring generation of Th1 effectors and their trafficking to the frontline of infection to program microbial killing by inflammatory monocytes.

【 授权许可】

CC BY