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

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. © 2013 cohen et al.