Inhibition of endogenous MHC class II‐restricted antigen presentation by tacrolimus (FK506) via FKBP51

Abstract

The effect of tacrolimus (FK506) on down-regulation of IL-2 production by T cells is considered to be mainly responsible for its strong suppression of immunological events. In this study, we show that FK506 also has an affect on antigen presentation by antigenpresenting cells in vitro. FK506 was able to inhibit the presentation of endogenous MHC class II-restricted minor histocompatibility antigens in primary dendritic cells (DC) in vitro, but cyclosporine A (CsA) and rapamycin (RAP) were not. RNA interference (RNAi)-mediated reduction of endogenous FK506-binding protein (FKBP)51 expression resulted in a marked decrease in antigen presentation, suggesting that FKBP51 plays a role in endogenous MHC class II-restricted antigen presentation. Since our model used naturally expressed cytosolic antigens in primary DC, these effects might have been due to novel properties of the immunosuppressive drugs and may allow us to elucidate a new paradigm for the immunosuppressive mechanism of FK506.

Dendritic Cells and Macrophages

“…Table 2 lists additional receptors important in CKD with the potential to modify DC or macrophage activation. Some of the immunosuppressive agents used to prevent transplant rejection prevented DC activation in vitro (for example, sirolimus [112] and tacrolimus [113]). However, their usefulness in CKD is limited by side effects.…”

Gag- and Nef-specific CD4+T cells recognize and inhibit SIV replication in infected macrophages early after infection

“…Then, at various time points after infection, we treated the MDM with the calcineurin inhibitor FK-506 to block the transport of newly epitope-loaded MHC-II molecules to the cell surface. FK-506 has been previously shown to block presentation of both exogenous and endogenous antigen while not interfering with T cell cytokine secretion (24,25). Therefore, addition of 4 nM FK-506 effectively paused MHC-II antigen presentation, allowing us to assess the kinetics of MHC-II antigen presentation in detail.…”

EpsinR, a target for pyrenocine B, role in endogenous MHC‐II‐restricted antigen presentation

“…We have previously reported that the murine H46 locus on chromosome 7 encoded the interleukin 4-induced gene 1 (IL4I1), and this antigen was endogenously expressed in bone marrow-derived DCs (BMDCs) in the context of MHC class II (I-A b ) molecules using the IL4I1-specific recognized lacZ-inducible CD4 + T-cell hybridoma TH3Z [13]. In addition, it was reported that FKBP51 molecules play an important role for MHC class II-restricted IL4I1 antigen presentation using the same model [14].…”

“…We have previously reported that the murine H46 locus on chromosome 7 encoded the interleukin 4-induced gene 1 (IL4I1), and this antigen was endogenously expressed in bone marrow-derived DCs (BMDCs) in the context of MHC class II (I-A b ) molecules using the IL4I1-specific recognized lacZ-inducible CD4 + T-cell hybridoma TH3Z [13]. In addition, it was reported that FKBP51 molecules play an important role for MHC class II-restricted IL4I1 antigen presentation using the same model [14].In order to better understand the antigen presentation machinery, we used a chemical biology approach that explored the chemical compounds derived from a natural product with inhibitory effects of antigen presentation and identified its target molecules by using phage display screening. In this study, we found that pyrenocine B, which is derived from the fungus Pyrenochaeta terrestris inhibits presentation of endogenous MHC class IIrestricted antigens in BMDCs in vitro.…”

“…The IL4I1-specific lacZ inducible CD4 + T-cell hybrid TH3Z (B6 mousederived-IL4I1567-580/I-A b -specific) was generated as described [22]. The lacZ inducible CD4 + T-cell hybrid KZO (ovalbumin (OVA) 247-265/A k specific) and KZH (HEL 34-45/ A k specific) were used to investigate effect of pyrenocine B on exogenous antigen presentation as described elsewhere [14,30]. …”