CXCR3-dependent CD4⁺ T cells are required to activate inflammatory monocytes for defense against intestinal infection.

Abstract

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.

• Authors: Sara B Cohen, Kirk J Maurer, Charlotte E Egan, Steve Oghumu, Abhay R Satoskar, Eric Y Denkers
• Journal: PLoS pathogens (PLoS Pathog) Vol. 9 Issue 10 Pg. e1003706 ( 2013) ISSN: 1553-7374 [Electronic] United States
• PMID: 24130498 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cxcr3 protein, mouse
• Receptors, CXCR3
• Interferon-gamma

Topics

• Animals
• CD8-Positive T-Lymphocytes (immunology, pathology)
• Immunity, Cellular
• Immunity, Innate
• Interferon-gamma (genetics, immunology)
• Intestinal Diseases (genetics, immunology, pathology)
• Mice
• Mice, Knockout
• Monocytes (immunology, pathology)
• Receptors, CXCR3 (genetics, immunology)
• Th1 Cells (immunology, pathology)
• Toxoplasma (immunology)
• Toxoplasmosis (genetics, immunology, pathology)