Modulation of dendritic cell immunobiology via inhibition of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase.

Tina Leuenberger,Frauke Zipp,Josephine Herz,Carmen Infante-Duarte,Magdalena Paterka,Denise Treue,Timour Prozorovski,Sonia Waiczies,Caspar F Pfueller,Ivo Bendix,Felix Luessi,Sarah Luenstedt,Volker Siffrin,Heinz Wiendl

doi:10.1371/journal.pone.0100871

Abstract

The maturation status of dendritic cells determines whether interacting T cells are activated or if they become tolerant. Previously we could induce T cell tolerance by applying a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor (HMGCRI) atorvastatin, which also modulates MHC class II expression and has therapeutic potential in autoimmune disease. Here, we aimed at elucidating the impact of this therapeutic strategy on T cell differentiation as a consequence of alterations in dendritic cell function. We investigated the effect of HMGCRI during differentiation of peripheral human monocytes and murine bone marrow precursors to immature DC in vitro and assessed their phenotype. To examine the stimulatory and tolerogenic capacity of these modulated immature dendritic cells, we measured proliferation and suppressive function of CD4+ T cells after stimulation with the modulated immature dendritic cells. We found that an HMGCRI, atorvastatin, prevents dendrite formation during the generation of immature dendritic cells. The modulated immature dendritic cells had a diminished capacity to take up and present antigen as well as to induce an immune response. Of note, the consequence was an increased capacity to differentiate naïve T cells towards a suppressor phenotype that is less sensitive to proinflammatory stimuli and can effectively inhibit the proliferation of T effector cells in vitro. Thus, manipulation of antigen-presenting cells by HMGCRI contributes to an attenuated immune response as shown by promotion of T cells with suppressive capacities.

Highlights

Bidirectional interactions between dendritic cells (DC) as professional antigen-presenting cells (APC) and T cells may result in either promotion or suppression of immune responses, depending on the environmental cues
Cytoskeletal alterations in immature DC (iDC) generated in the presence of atorvastatin
In the human system (Fig 1A) we co-stained for CD11c and found that increasing atorvastatin concentrations affected CD11c localization; while CD11c is normally diffusely co-expressed with f-actin on cytoplasmic processes and at sites of intercellular contact in DC [19], a more compact and nucleus-associated CD11c signal was observed in atorvastatin during the generation of iDC (aiDC) with increasing atorvastatin concentrations (Fig 1A)

Summary

Introduction

Bidirectional interactions between dendritic cells (DC) as professional antigen-presenting cells (APC) and T cells may result in either promotion or suppression of immune responses, depending on the environmental cues. In the peripheral circulation resting or immature DC (iDC) have a high capacity for taking up antigen but low capacity for binding and stimulating T cells [1]. In the presence of an inflammatory milieu, iDC transform into mature DC that exhibit a limited capacity for taking up antigen but exceptional capacity at stimulating T cells [2,3]. One strategy introduced at the turn of this century was to expose autologous DC to antigen in the absence of a maturation signal and transplant them back to induce regulatory T cells in vivo [8,9]. The first EAE study reported on a reduction in Th1 differentiation in myelin-reactive CD4+ T cells following atorvastatin treatment as well as a regulation of the APC compartment, which subsequently influenced the T cell response [13]. Our group reported on a direct influence of atorvastatin on the anergic status [14] and cytoskeletal reorganization [15] of T cells as possible mechanisms for the salutary role of atorvastatin treatment

Methods

Results

Conclusion