Maturation Of iNKT Cells Research Articles

The Wiskott-Aldrich syndrome protein is required for iNKT cell maturation and function

The Wiskott-Aldrich syndrome (WAS) protein (WASp) is a regulator of actin cytoskeleton in hematopoietic cells. Mutations of the WASp gene cause WAS. Although WASp is involved in various immune cell functions, its role in invariant natural killer T (iNKT) cells has never been investigated. Defects of iNKT cells could indeed contribute to several WAS features, such as recurrent infections and high tumor incidence. We found a profound reduction of circulating iNKT cells in WAS patients, directly correlating with the severity of clinical phenotype. To better characterize iNKT cell defect in the absence of WASp, we analyzed was−/− mice. iNKT cell numbers were significantly reduced in the thymus and periphery of was−/− mice as compared with wild-type controls. Moreover analysis of was−/− iNKT cell maturation revealed a complete arrest at the CD44+ NK1.1− intermediate stage. Notably, generation of BM chimeras demonstrated a was−/− iNKT cell-autonomous developmental defect. was−/− iNKT cells were also functionally impaired, as suggested by the reduced secretion of interleukin 4 and interferon γ upon in vivo activation. Altogether, these results demonstrate the relevance of WASp in integrating signals critical for development and functional differentiation of iNKT cells and suggest that defects in these cells may play a role in WAS pathology.

Enhanced Early Expansion and Maturation of Semi-Invariant NK T Cells Inhibited Autoimmune Pathogenesis in Congenic Nonobese Diabetic Mice

Semi-invariant NK T cell (iNKT) deficiency has long been associated with the pathogenesis of type 1 diabetes (T1D), but the linkage between this the deficiency and T1D susceptibility gene(s) remains unclear. We analyzed NOD mice subcongenic for resistant alleles of Idd9 locus in search for protective mechanisms against T1D, and found that iNKT cell development was significantly enhanced with a more advanced mature phenotype and function in mice containing Idd9.1 sublocus of B10 origin. The enhanced iNKT cell development and function suppressed effector function of diabetogenic T cells. Elimination of iNKT cells by CD1d deficiency almost abolished T1D protection in these mice. Interestingly, although the iNKT cells were responsible for a Th2 orientated cytokine profile that is often regarded as a mechanism of T1D prevention, our data suggests that the Th2 bias played little if any role for the protection. In addition, dendritic cells from the congenic NOD mice showed increased abilities to engage and potentiate iNKT cells, suggesting that a mechanism mediated by dendritic cells or other APCs may be critical for the enhanced development and maturation of iNKT cells. The products of T1D susceptibility gene(s) in Idd9.1 locus may be a key factor for this mechanism.

Osteopontin regulates development and function of invariant natural killer T cells

Invariant natural killer T (iNKT) cells belong to a subset of lymphocytes bridging innate and acquired immunity. We demonstrated that osteopontin (OPN) is involved in the activation of iNKT cells. In the present work, we examined whether OPN affects development and function of iNKT cells. We found that the number of peripheral iNKT cells was significantly reduced in OPN-deficient mice compared with wild-type mice. Although the number of thymic iNKT cells was not different between WT and OPN-deficient mice, intrathymic iNKT cell maturation was impaired in OPN-deficient mice. iNKT cell function was also significantly altered in OPN-deficient mice, as evidenced by (i) deficient down-regulation of iNKT cell receptor, (ii) reduction of IL-4 production while preserving production of IFN-gamma, and (iii) reduction of Fas ligand (FasL) expression, leading to reduced Fas/FasL-dependent cytotoxicity against hepatocytes. Importantly, activation of the transcription factors NFAT2 (nuclear factor of activated T cells 2) and GATA-3 was impaired, whereas activation of T-bet was preserved in iNKT cells of OPN-deficient mice. These data collectively indicate that OPN plays a pivotal role not only in the development, but also in the function of iNKT cells.

The kinase activity of ITK is not required for iNKT cell development and function

Invariant natural killer T (iNKT) cells are a unique subset of innate T lymphocytes that are selected by CD1d. They have diverse immune regulatory functions via the rapid production of interferon‐gamma (IFN‐gamma) and interleukin‐4 (IL‐4). In the absence of ITK, a Tec family non‐receptor tyrosine kinase, mice exhibit a significant defect in iNKT cell development, and residual iNKT cells have defective cytokine secretion. Although the kinase activity is important for ITK, several studies have shown that ITK can activate pathways that are independent of its kinase activity. Whether the requirement for ITK in iNKT cells development and function is dependent on its kinase activity is not clear. We report here that the kinase activity of ITK is not fully required for the mature and activation of iNKT cells. In mice which carry a kinase‐domain deleted ITK in the ITK null background (ItkΔKinTg/Itk−/ −), we observe significant rescue of mature iNKT cells in the thymus and spleen compared with ITK null mice. Furthermore, unlike ITK−/ − iNKT cells, iNKT cells from ItkΔKinTg/Itk−/ − mice were able to secrete IFN‐gamma and IL‐4 upon exposure to α‐GalCer. These data indicate that ITK uses a scaffolding function in the signaling pathway leading to the maturation and activation of iNKT cells.

A Critical Role of Costimulation during Intrathymic Development of Invariant NK T Cells

CD1d-restricted Valpha14(+) invariant NK T (iNKT) cells are a specialized alphabeta T cell subset that regulates both innate and adaptive immunity. Although costimulatory molecules are required for the activation of conventional T cells and for the development of Foxp3(+) T cells, their role in iNKT cell regulation is unclear. Here we report that mice deficient in CD80/CD86 and/or B7h exhibit severe defects in thymic iNKT cell maturation, associated with largely reduced iNKT cell number in the thymus and the periphery. We show that costimulation is necessary for the optimal expansion of postselected NK1.1(-) immature iNKT cells in the thymus and for the proper expression of the maturation markers T-bet and CD122. Surprisingly, costimulatory molecules on both hemopoietic and nonhematopoietic cells are required for iNKT cell development. Our results thus demonstrate a previously unknown function of costimulation in the intrathymic development of iNKT cells, distinct from that of conventional T cells and regulatory T cells.

A Failure to Launch: Fuelling Cytokine Secretion in iNKT Cells

In this issue of Immunity, Bezbradica et al., (2006) uncover an unsuspected role for the cytokine GM-CSF in the thymic development of invariant NKT cells, a role that licenses these cells to secrete effector cytokines upon activation in the periphery.

Rapidly expanding exophthalmos: an unusual presentation of small cell lung cancer.

A 61-year-old male presented with a rapidly progressive exophthalmos from small cell lung cancer metastatic to the right orbit. His vision in that eye was 20/200, and his intraocular pressure was 36 mmHg. The orbital metastasis responded dramatically to chemotherapy. One week after starting the chemotherapy the patient did not have exophthalmos, his vision was 20/20, and three weeks later the intraocular pressure was 12 mmHg.