Modulation of Valpha19 NKT cell immune responses by alpha-mannosyl ceramide derivatives consisting of a series of modified sphingosines.
We have demonstrated that analogues of alpha-mannosyl ceramide (alpha-ManCer) consisting of a series of immunosuppressive 2-aminoalcohol derivatives in place of sphingosine promote a greater immune response from mouse invariant Valpha19-Jalpha26 (AV19-AJ33) TCR-bearing NKT (Valpha19 NKT) cells than alpha-ManCer itself. To further characterize the immune responses of Valpha19 NKT cells to the alpha-ManCer analogues, cytokine production by the cells was examined in detail. We found that certain alpha-ManCer derivatives individually induced either Th1- or Th2-dominant cytokine production in culture. The Th1- or Th2-biased immune responses of Valpha19 NKT cells were dependent on MHC class I-like MR1, since they were induced by coculture with the MR1 transfectants previously loaded with the glycolipids and were inhibited in the presence of anti-MR1 antiserum. Presumably, the recognition of the alpha-mannosyl residue of the alpha-ManCer analogues by the invariant TCR is individually modulated, depending on the altered interaction with the groove of the antigen-presenting MR1. Priming of the Valpha19 invariant TCR-transgenic mice in vivo with these glycolipid derivatives resulted in the induction of the Th1- or Th2-biased immune responses. Thus, these alpha-ManCer derivatives are likely to be useful in immunotherapy for either Th1 or Th2 excess autoimmune diseases, modulating the function of Valpha19 NKT cells.
Shimamura
Michio
M
Developmental Immunology Unit, Mitsubishi Kagaku Institute of Life Sciences, Tokyo; Japan. michio@libra.ls.m-kagaku.co.jp
Huang
Yi-Ying
YY
Okamoto
Naoki
N
Suzuki
Nahoko
N
Yasuoka
Jouji
J
Morita
Kenji
K
Nishiyama
Akira
A
Amano
Yuusuke
Y
Mishina
Tadashi
T
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D002478:Cells, Cultured; D002518:Ceramides / Q000737:chemistry / Q000276:immunology; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D006028:Glycosphingolipids / Q000737:chemistry / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D015778:Minor Histocompatibility Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D013110:Sphingosine / Q000737:chemistry / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014162:Transfection
D002518:Ceramides; D016207:Cytokines; D006028:Glycosphingolipids; D015395:Histocompatibility Antigens Class I; C094840:MR1 protein, human; D015778:Minor Histocompatibility Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D013110:Sphingosine