Wortmannin, an inhibitor of phospholipase D activation, selectively blocks major histocompatibility complex class II-restricted antigen presentation
✍ Scribed by Eugenio Carrasco-Marín; Carmen Alvarez-Domínguez; Francisco Leyva-Cobián
- Publisher
- John Wiley and Sons
- Year
- 1994
- Tongue
- English
- Weight
- 991 KB
- Volume
- 24
- Category
- Article
- ISSN
- 0014-2980
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✦ Synopsis
Wortmannin blocks antigen presentation 2031
Wortmannin, an inhibitor of phospholipase D activation, selectively blocks major histocompatibility complex class 11-restricted antigen presentation* Wortmannin, a fungal metabolite, is a specific inhibitor of phospholipase D (PLD) activation. Presentation of defined exogenous soluble proteins to specific T cell hybridomas was studied by using different antigen-presenting cells (APC): IA-positive peritoneal macrophages (Ma), B lymphoma cells (B) or dendritic cells (DC). Major histocompatibility complex class 11-restricted antigen presentation by M@ was blocked when cells were pretreated with wortmannin. However, when cells constitutively expressing IA molecules (B, DC) were used as APC, no inhibition was observed. Additionally, MHC class I antigen presentation was not impaired by wortmannin. Moreover, wortmannin does not block either peptide presentation or presentation to autoreactiveT cells. This effect was time and dose dependent and occurred at the level of intracellular handling of the antigen. Mainly because it was not a toxic inhibition, it was reversible with time and neither antigen uptake and catabolism, nor IA synthesis were affected. Because M@, but not B or DC, express PLD activity and only the former were blocked by wortmannin in antigen presentation, our results strongly suggest that a differential antigen-processing pathway exists in these disparate APC, which could be based essentially on a wortmannin-sensitive, PLD-dependent step present in M@ but absent andlor unnecessary in both B lymphoma cells and DC.
1 Introdution
A fundamental issue in antigen presentation is the elucidation of the specific intracellular steps in antigen processing. An approach to understanding the biochemical events that occur during intracellular processing was to use defined chemicals that block essential steps necessary for correct antigen presentation. Classically, it was shown that lysosomotropic agents (chloroquine, NKCI) that raise the pH of endocytic structures abolish class I1 antigen presentation, leaving class I presentation unaffected [l, 21. Recently, a