Overexpression of CD1d by Keratinocytes in Psoriasis and CD1d-Dependent IFN-γ Production by NK-T Cells

IFN-γ mediates chemically induced skin inflammation; however, the mechanism by which IFN-γ–producing cells are recruited to the sites of inflammation remains undefined. Secretion of macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, from damaged cells may promote immune cell recruitment. We hypothesized that MIF triggers an initial step in the chemotaxis of IFN-γ–producing cells in chemically induced skin inflammation. Using acute and chronic models of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation in mouse ears, MIF expression was examined, and its role in this process was investigated pharmacologically. The cell populations targeted by MIF, their receptor expression patterns, and the effects of MIF on cell migration were examined. TPA directly caused cytotoxicity accompanied by MIF release in mouse ear epidermal keratinocytes, as well as in human keratinocytic HaCaT cells. Treatment with the MIF antagonist (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester considerably attenuated TPA-induced ear swelling, leukocyte infiltration, epidermal cell proliferation, and dermal angiogenesis. Inhibition of MIF greatly diminished the dermal infiltration of IFN-γ+ NKT cells, whereas the addition of exogenous TPA and MIF to NKT cells promoted their IFN-γ production and migration, respectively. MIF specifically triggered the chemotaxis of NKT cells via CD74 and CXCR2, and the resulting depletion of NKT cells abolished TPA-induced skin inflammation. In TPA-induced skin inflammation, MIF is released from damaged keratinocytes and then triggers the chemotaxis of CD74+CXCR2+ NKT cells for IFN-γ production.

Section: Discussionmentioning

confidence: 99%

Macrophage Migration Inhibitory Factor Triggers Chemotaxis of CD74+CXCR2+ NKT Cells in Chemically Induced IFN-γ–Mediated Skin Inflammation

Hsieh

Chen

Lin

et al. 2014

“…It has been previously shown that in vitro treatment with IFN-␥ can induce CD1d on keratinocytes, and enhanced expression of CD1d proteins was observed in psoriatic skin lesions, indicating that CD1d could be up-regulated on epithelial cells in the skin during the inflammation (23). To investigate the possibility that CD1d expression by Schwann cells can be similarly up-regulated, we cultured Schwann cell lines in medium containing a saturating amount of recombinant IFN-␥ for 48 h and examined the change in the level of surface CD1d expression by FACS.…”

Section: Up-regulation Of Schwann Cell Cd1d By Ifn-␥ Treatmentmentioning

confidence: 99%

“…Acetone-fixed sections of human nerve biopsy specimens were used for immunohistochemistry as previously described, and slides were counterstained with hematoxylin (23). Images were acquired and processed by immunofluorescence microscopy (Olympus).…”

Section: Immunostaining and Immunohistochemistrymentioning

confidence: 99%

“…CD1d proteins from soluble cell lysates were immunoprecipitated using mAb CD1d51 and deglycosylated by PNGase F treatment (New England Biolabs) (23). Western blotting was performed with a mixture of mAbs CD1d75, C3D5, and NOR3.2, followed by biotinylated goat anti-mouse -chain (Southern Biotechnology Associates) and streptavidin-poly-HRP (Bio-Rad).…”

Section: Immunoprecipitation and Western Blotting Of Cd1dmentioning

confidence: 99%

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Expression of CD1d Molecules by Human Schwann Cells and Potential Interactions with Immunoregulatory Invariant NK T Cells

Im¹,

Tapinos

Chae³

et al. 2006

Self Cite

CD1d-restricted NKT cells expressing invariant TCR α-chains (iNKT cells) produce both proinflammatory and anti-inflammatory cytokines rapidly upon activation, and are believed to play an important role in both host defense and immunoregulation. To address the potential implications of iNKT cell responses for infectious or inflammatory diseases of the nervous system, we investigated the expression of CD1d in human peripheral nerve. We found that CD1d was expressed on the surface of Schwann cells in situ and on primary or immortalized Schwann cell lines in culture. Schwann cells activated iNKT cells in a CD1d-dependent manner in the presence of α-galactosylceramide. Surprisingly, the cytokine production of iNKT cells stimulated by α-galactosylceramide presented by CD1d+ Schwann cells showed a predominance of Th2-associated cytokines such as IL-5 and IL-13 with a marked deficiency of proinflammatory Th1 cytokines such as IFN-γ or TNF-α. Our findings suggest a mechanism by which iNKT cells may restrain inflammatory responses in peripheral nerves, and raise the possibility that the expression of CD1d by Schwann cells could be relevant in the pathogenesis of infectious and inflammatory diseases of the peripheral nervous system.

“…The group 2 CD1 molecule, CD1d, is expressed in both murine and human tissues. In humans, CD1d is found on a subset of B cells, thymocytes, and myeloid-lineage cells, gastrointestinal epithelium, and skin (5,6).…”

mentioning

confidence: 99%

Human NKT Cells Express Granulysin and Exhibit Antimycobacterial Activity

Gansert

Kieβler

Engele

et al. 2003

Self Cite

165

138

Human NKT cells are a unique subset of T cells that express an invariant Vα24 TCR that recognizes the nonclassical Ag-presenting molecule CD1d. Activation of NKT cells is greatly augmented by the marine sponge-derived glycolipid α-galactosylceramide (αGalCer). Because human monocyte-derived cells express CD1d and can harbor the intracellular pathogen Mycobacterium tuberculosis, we asked whether the addition of αGalCer could be used to induce effector functions of NKT cells against infected monocytes, macrophages, and monocyte-derived dendritic cells. NKT cells secreted IFN-γ, proliferated, and exerted lytic activity in response to αGalCer-pulsed monocyte-derived cells. Importantly, αGalCer-activated NKT cells restricted the growth of intracellular M. tuberculosis in a CD1d-dependent manner. NKT cells that exhibited antimycobacterial activity also expressed granulysin, an antimicrobial peptide shown to mediate an antimycobacterial activity through perturbation of the mycobacterial surface. Degranulation of NKT cells resulted in depletion of granulysin and abrogation of antimycobacterial activity. The detection of CD1d in granulomas of tuberculosis patients supports the potential interaction of NKT cells with CD1d-expressing cells at the site of disease activity. These studies provide evidence that αGalCer-activated CD1d-restricted T cells can participate in human host defense against M. tuberculosis infection.