Critical Role for the Chemokine Receptor CXCR6 in Homeostasis and Activation of CD1d-Restricted NKT Cells

Abstract

NK T (NKT) cells play important roles in the regulation of diverse immune responses. However, little is known about the mechanisms that regulate homeostasis and activation of these cells. Thymic NKT cells up-regulated the chemokine receptor CXCR6 following positive selection and migrated toward CXCL16 in vitro. However, CXCR6 was not essential for thymic development or maturation. In contrast, liver and lung NKT cells were depleted in CXCR6+/− and CXCR6−/− mice. The reduction in liver and lung NKT cells coincided with an increase in bone marrow NKT cells, suggesting a redistribution of NKT cells in CXCR6−/− animals. In wild-type mice, CXCL16 neutralization reduced accumulation of mature NK1.1+, but not immature NK1.1− NKT cell recent thymic emigrants in the liver. Given that thymic NKT cells are preferentially exported as NK1.1− cells, this suggests an additional role for CXCR6/CXCL16 in maturation or survival of immature liver NKT cells. CXCL16 blockade did not deplete resident NK1.1+ NKT cells, indicating that CXCR6/CXCL16 are not required to retain mature NKT cells in the liver. Cytokine production by liver and spleen NKT cells was impaired in CXCR6−/− mice following in vivo stimulation with α-galactosylceramide, implicating a novel role for CXCR6 in NKT cell activation. Reduced IFN-γ production was not due to an intrinsic defect as production was normal following PMA and ionomycin stimulation. Preformed transcripts for IL-4, but not IFN-γ, were reduced in CXCR6−/− liver NKT cells. These data identify critical roles for CXCR6/CXCL16 in NKT cell activation and the regulation of NKT cell homeostasis.

Enhanced Tumor Metastasis in Response to Blockade of the Chemokine Receptor CXCR6 Is Overcome by NKT Cell Activation

“…Furthermore, CXCL16 has been shown to mediate the accumulation of iNKT cells in allogeneic cardiac allografts (33). In addition to regulating iNKT cell homing, CXCR6 and CXCL16 have been shown to play a critical role in iNKT cell activation in response to glycolipid Ags (31,32). As CXCL16 is expressed as a transmembrane protein on the surface of APCs (32), it is likely that CXCR6 and CXCL16 mediate costimulatory interactions between iNKT cells and glycolipid-presenting dendritic cells (DCs) that modulate activation and effector functions.…”

“…Ϫ/Ϫ mice are known to have reduced numbers of mature iNKT cells in the liver and lungs (30,31), allowing us to test whether CXCR6 or normal iNKT cell localization are required to protect these tissues from tumor metastasis. B16 melanoma cells were inoculated into the spleens of wild-type and CXCR6 Ϫ/Ϫ mice, leading to preferential liver metastasis via the portal circulation (35).…”

Type I natural killer T cells: naturally born for fighting

“…NKT cells directly eradicate target cells through cell death inducing ligands FasL and TNF-related apoptotic induced ligand (TRAIL) [69] . The recruitment of leukocytes into tissues is dependent on a series of adhesive and activation steps mediated by adhesion molecules and interaction of chemokine and chemokine receptors, which restrict their tissue and microenvironmental distribution [70][71][72] . In this regard, NKT cells resemble effector T cells because CD4 + , CD8 + , and DN subsets uniformly express non-lymphoidtissue-homing chemokine receptors, such as CCR2, CCR5, and CXCR3 [70] .…”

Notch Signaling Regulates the Homeostasis of Tissue-Restricted Innate-like T Cells

“…Transcription factors such as Id2 show selective roles in the survival of hepatic iNKTs. Likewise, mice deficient for either CXCR6 or CXCL16 show a selective loss of hepatic iNKTs, but unperturbed thymic and splenic iNKT cell compartments (16). Moreover, common g-chain (g c ) cytokines, including IL-15, are known to regulate the terminal stages of thymic iNKT differentiation, maturation, survival, and peripheral homeostasis (17).…”

“…After thymic selection, they undergo programmed differentiation characterized by progressive acquisition of NK markers and effector functions (14). Once iNKTs are fully mature, they migrate by chemotaxis to the periphery in a CXCR3-dependent manner, or to the liver in a CXCR6-dependent manner (15,16). Many signaling molecules including transcription factors, cytokines, and chemokines are known to play vital roles in iNKT development, maturation, survival, and homing.…”