RESUMO
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.
Assuntos
Glicoesfingolipídeos/imunologia , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Apresentação de Antígeno/imunologia , Células Cultivadas , Ceramidas/química , Ceramidas/imunologia , Técnicas de Cocultura , Citocinas/biossíntese , Glicoesfingolipídeos/química , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Ativação Linfocitária/imunologia , Camundongos , Antígenos de Histocompatibilidade Menor , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Esfingosina/química , Esfingosina/imunologia , TransfecçãoRESUMO
A 2-substituted 2-aminopropane-1,3-diol or 2-aminoethanol is the minimum structure required for the immunosuppressive activity of ISP-I, an antibiotic isolated from the culture broth of Isaria sinclairil. A series of alpha-mannosyl ceramide (alpha-ManCer) analogues was derived from 2-substituted 2-aminopropane-1,3-diols or 2-aminoethanols in place of sphingosine. The newly synthesized glycosides were evaluated for their effects on immune responses. In contrast to the immunosuppressive activity of the precursors, the alpha-ManCer analogues induced immunopromotive responses from invariant Valpha19-Jalpha26 transgenic mouse lymphocytes more effectively than the original alpha-ManCer. Collectively, it is strongly suggested that the 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols mimic sphingosine in the alpha-ManCer analogues so that they potentially acquire specific antigenicity toward Valpha19 NKT cell, a novel NKT cell subset.