Cerebral malaria is a significant cause of global mortality, causing an estimated two million deaths per year, mainly in children. The pathogenesis of this disease remains incompletely understood. Chemokines have been implicated in the development of cerebral malaria, and the IFN-inducible CXCR3 chemokine ligand IP-10 (CXCL10) was recently found to be the only serum biomarker that predicted cerebral malaria mortality in Ghanaian children. We show that the CXCR3 chemokine ligands IP-10 and Mig (CXCL9) were highly induced in the brains of mice with murine cerebral malaria caused by Plasmodium berghei ANKA. Mice deficient in CXCR3 were markedly protected against cerebral malaria and had far fewer T cells in the brain compared with wild-type mice. In competitive transfer experiments, CXCR3-deficient CD8 ⁺ T cells were 7-fold less efficient at migrating into the infected brains than wild-type CD8 ⁺ T cells. Adoptive transfer of wild-type CD8 ⁺ effector T cells restored susceptibility of CXCR3-deficient mice to cerebral malaria and also restored brain proinflammatory cytokine and chemokine production and recruitment of T cells, independent of CXCR3. Mice deficient in IP-10 or Mig were both partially protected against cerebral malaria mortality when infected with P. berghei ANKA. Brain immunohistochemistry revealed Mig staining of endothelial cells, whereas IP-10 staining was mainly found in neurons. These data demonstrate that CXCR3 on CD8 ⁺ T cells is required for T cell recruitment into the brain and the development of murine cerebral malaria and suggest that the CXCR3 ligands Mig and IP-10 play distinct, nonredundant roles in the pathogenesis of this disease.

Innate-like NKT cells conspicuously accumulate within the liver microvasculature of healthy mice, crawling on the luminal side of endothelial cells, but their general recirculation pattern and the mechanism of their intravascular behavior have not been elucidated. Using parabiotic mice, we demonstrated that, despite their intravascular location, most liver NKT cells failed to recirculate. Antibody blocking experiments established that they were retained locally through constitutive LFA-1–intercellular adhesion molecule (ICAM) 1 interactions. This unprecedented lifelong intravascular residence could be induced in conventional CD4 T cells by the sole expression of promyelocytic leukemia zinc finger (PLZF), a transcription factor specifically expressed in the NKT lineage. These findings reveal the unique genetic and biochemical pathway that underlies the innate intravascular surveillance program of NKT cells.

CD1d-restricted T cells (NKT cells) are innate memory cells activated by lipid Ags and play important roles in the initiation and regulation of the immune response. However, little is known about the trafficking patterns of these cells or the tissue compartment in which they exert their regulatory activity. In this study, we determined the chemokine receptor profile expressed by CD1d-restricted T cells found in the peripheral blood of healthy volunteers as well as CD1d-restricted T cell clones. CD1d-restricted T cells were identified by Abs recognizing the invariant Vα24 TCR rearrangement or by binding to CD1d-Fc fusion tetramers loaded with α-GalCer. CD1d-restricted T cells in the peripheral blood and CD1d-restricted T cell clones expressed high levels of CXCR3, CCR5, and CCR6; intermediate levels of CXCR4 and CXCR6; and low levels of CXCR1, CCR1, CCR2, and CX₃CR1, a receptor pattern often associated with tissue-infiltrating effector Th1 cells and CD8⁺ T cells. Very few of these cells expressed the lymphoid-homing receptors CCR7 or CXCR5. CCR4 was expressed predominantly on CD4⁺, but not on double-negative CD1d-restricted T cells, which may indicate differential trafficking patterns for these two functionally distinct subsets. CD1d-restricted T cell clones responded to chemokine ligands for CXCR1/2, CXCR3, CXCR4, CXCR6, CCR4, and CCR5 in calcium flux and/or chemotaxis assays. These data indicate that CD1d-restricted T cells express a chemokine receptor profile most similar to Th1 inflammatory homing cells and suggest that these cells perform their function in peripheral tissue sites rather than in secondary lymphoid organs.

The host response to intracellular pathogens requires the coordinated action of both the innate and acquired immune systems. Chemokines play a critical role in the trafficking of immune cells and transitioning an innate immune response into an acquired response. We analyzed the host response of mice deficient in the chemokine receptor CCR5 following infection with the intracellular protozoan parasite Toxoplasma gondii. We found that CCR5 controls recruitment of natural killer (NK) cells into infected tissues. Without this influx of NK cells, tissues from CCR5-deficient (CCR5^−/−) mice were less able to generate an inflammatory response, had decreased chemokine and interferon γ production, and had higher parasite burden. As a result, CCR5^−/− mice were more susceptible to infection with T. gondii but were less susceptible to the immune-mediated tissue injury seen in certain inbred strains. Adoptive transfer of CCR5^+/+ NK cells into CCR5^−/− mice restored their ability to survive lethal T. gondii infection and demonstrated that CCR5 is required for NK cell homing into infected liver and spleen. This study establishes CCR5 as a critical receptor guiding NK cell trafficking in host defense. Toxoplasma gondii, an obligate intracellular parasite, evokes a strong cellular immune response, which is critical for host protection. Chemokines and their receptors control the trafficking of immune cells to sites of infection. In this study, the authors examined the immune response to T. gondii in mice deficient in the chemokine receptor CCR5. CCR5-deficient mice exhibited a decreased inflammatory response, which led to a higher parasite burden and ultimate mortality. The deficiency in the immune response in CCR5-deficient mice was the result of decreased migration of natural killer (NK) cells into infected tissues. Transfer of normal NK cells into CCR5-deficient mice restored NK cell homing into infected tissue and the normal immune response capable of controlling T. gondii infection. These findings demonstrate an important role for CCR5 in trafficking the NK cells during acute T. gondii infection. Furthermore, since CCR5 is the main co-receptor for HIV-1 entry into cells, the results of this study raise a concern about the potential complication of impaired NK cell function in the clinical use of CCR5 antagonists, currently being developed as therapeutics for HIV-1 and inflammatory diseases. This may be of particular concern for HIV-1-infected patients coinfected with T. gondii or for those who acquire an acute T. gondii infection while taking a CCR5 antagonist.

T cells are critical mediators of the allergic airway inflammation seen in asthma. Pathogenic allergen-specific T cells are generated in regional lymph nodes and are then recruited into the airway by chemoattractants produced by the asthmatic lung. These recruited effector T cells and their products then mediate the cardinal features of asthma: airway eosinophilia, mucus hypersecretion, and airway hyperreactivity. There has been considerable progress in delineating the molecular mechanisms that control T cell trafficking into peripheral tissue, including the asthmatic lung. In this review, we summarize these advances and formulate them into a working model that proposes that T cell trafficking into and out of the allergic lung is controlled by several discrete regulatory pathways that involve the collaboration of innate and acquired immune cells.