title: 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.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America.
authors.forename: Sara B
authors.initials: SB
authors.lastname: Cohen
authors.forename: Kirk J
authors.initials: KJ
authors.lastname: Maurer
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Egan
authors.forename: Steve
authors.initials: S
authors.lastname: Oghumu
authors.forename: Abhay R
authors.initials: AR
authors.lastname: Satoskar
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Denkers
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D007111:Immunity, Cellular; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007410:Intestinal Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D014122:Toxoplasma / Q000276:immunology*; D014123:Toxoplasmosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D007371:Interferon-gamma