A Subset of NKT Cells That Lacks the NK1.1 Marker, Expresses CD1d Molecules, and Autopresents the α-Galactosylceramide Antigen

Pulmonary fibrosis is an end-stage disorder for which efficacious therapeutic options are not readily available. Although its pathogenesis is poorly understood, pulmonary fibrosis occurs as a result of various inflammations. NKT cells modulate inflammation because of their ability to produce large amounts of cytokines by stimulation with their glycolipid ligand. In the present study, we investigated the effects of α-galactosylceramide (α-GalCer), a selective NKT cell ligand, on the development of bleomycin-induced pulmonary fibrosis. Treatment of mice with α-GalCer prolonged their survival under bleomycin administration by attenuating the development of pulmonary fibrosis. The protective effects of α-GalCer were associated with an increase in the pulmonary level of IFN-γ and a decrease in the pulmonary level of fibrogenic cytokines such as TGF-β and connective tissue growth factor. The initial pulmonary inflammation caused by bleomycin was also attenuated by α-GalCer with the reduction of the macrophage inflammatory protein-2 level. The protective effects of α-GalCer were markedly reduced in mice lacking NKT cells or as a result of treatment with anti-IFN-γ Ab. These results suggest that α-GalCer suppresses bleomycin-induced acute pulmonary inflammation and thus attenuates the development of pulmonary fibrosis possibly by regulating several cytokine levels.

Section: Discussionmentioning

confidence: 57%

“…Several studies have demonstrated that NKT cells participate in several immune and inflammatory responses because of their remarkable capacity to produce immunoregulatory cytokines such as IFN-␥ and IL-4 after stimulation with either anti-CD3 (7,8) or their glycolipid ligand (9,10).…”

Section: Treatment With ␣-Galactosylceramide Attenuates the Developmementioning

confidence: 99%

Treatment with α-Galactosylceramide Attenuates the Development of Bleomycin-Induced Pulmonary Fibrosis

Kimura

Ishii

Morishima

et al. 2004

“…Recently, NK1.1 Ϫ T cells that bind CD1d tetramers have been detected in various tissues including the thymus, spleen, and lymph nodes (35), and our cultured NKT cells may represent these cells. A similar T cell subset was found to autopresent ␣-GalCer using CD1d on their own cell surface (40). Our NKT line also express CD1d, albeit at low level, and seem to autopresent ␣-GalCer as the cells are stimulated by the addition of ␣-GalCer without APCs (data not shown).…”

Section: Discussionmentioning

confidence: 77%

Regulation of NKT Cells by Ly49: Analysis of Primary NKT Cells and Generation of NKT Cell Line

Maeda

Lohwasser

Yamamura

et al. 2001

TCRαβ+NK1.1+ (NKT) cells are known to express various NK cell-associated molecules including the Ly49 family of receptors for MHC class I, but its functional significance has been unclear. Here, we examined the expression of Ly49A, C/I and G2 on various NKT cell populations from normal and MHC class I-deficient C57BL/6 mice as well as their responsiveness to α-galactosylceramide (α-GalCer), a potent stimulator of CD1d-restricted NKT cells. The frequency and the level of Ly49 expression varied among NKT cells from different tissues, and were regulated by the expression of MHC class I and CD1d in the host. Stimulation of various NKT cells with α-GalCer suggested that Ly49 expression inversely correlates with the responsiveness of NKT cells to α-GalCer. Moreover, α-GalCer presented by normal dendritic cells stimulated purified Ly49−, but not Ly49+, splenic NKT cells, whereas MHC class I-deficient dendritic cells presented α-GalCer to both Ly49+ and Ly49− NKT cells equally well. Therefore, MHC class I on APCs seems to inhibit activation of NKT cells expressing Ly49. To further characterize CD1d-restricted NKT cells, we generated an α-GalCer-responsive NKT cell line from thymocytes. The line could only be generated from Ly49−NK1.1+CD4+ thymocytes but not from other NKT cell subsets, and it lost expression of NK1.1 and CD4 during culture. Together, these results indicate the functional significance of Ly49 expression on NKT cells.

“…Although no increase in CD1d expression was observed on DP or APC subsets in the thymus or periphery, respectively, preliminary studies have found an increase in the expression of CD1d on the expanded NKT cell population in young B6.NZBc4L mice (our unpublished observations). It has been shown that CD1d-expressing NKT cells have the ability to autopresent ␣-galcer in the absence of APCs, raising the possibility that the expanded NKT cell population arises from autoactivation (41). Alternatively, altered T cell signaling may lead to the NKT cell expansion.…”

Section: Discussionmentioning

confidence: 99%

Dissociation of the Genetic Loci Leading to B1a and NKT Cell Expansions from Autoantibody Production and Renal Disease in B6 Mice with an Introgressed New Zealand Black Chromosome 4 Interval

Loh

Cai

Bonventi

et al. 2007

Previous mapping studies have linked New Zealand Black (NZB) chromosome 4 to several lupus traits, including autoantibody production, splenomegaly, and glomerulonephritis. To confirm the presence of these traits, our laboratory introgressed homozygous NZB chromosome 4 intervals extending from either 114 to 149 Mb or 32 to 149 Mb onto the lupus-resistant C57BL/6 background (denoted B6.NZBc4S and B6.NZBc4L, respectively). Characterization of aged cohorts revealed that B6.NZBc4L mice exhibited a striking increase in splenic B1a and NKT cells in the absence of high titer autoantibody production and significant renal disease. Tissue-specific expansion of these subsets was also seen in the peritoneum and liver for B1a cells and in the bone marrow for NKT cells. Staining with CD1d tetramers loaded with an α-galactosylceramide analog (PBS57) demonstrated that the expanded NKT cell population was mainly CD1d-dependent NKT cells. The lack of both cellular phenotypes in B6.NZBc4S mice demonstrates that the genetic polymorphism(s) that result in these phenotypes are on the proximal region of NZB chromosome 4. This study confirms the presence of a locus that promotes the expansion of B1a cells and newly identifies a region that promotes CD1d-restricted NKT cell expansion on NZB chromosome 4. Taken together, the data indicate that neither an expansion of B1a cells and/nor NKT cells is sufficient to promote autoantibody production and ultimately, renal disease.