Human Monocytes Differentiate into Dendritic Cells Subsets that Induce Anergic and Regulatory T Cells in Sepsis

Valérie Faivre,Didier Payen,Arnaud Alves,Alain Haziot,Dominique Charron,Anne Claire Lukaszewicz,Silke Appel

doi:10.1371/journal.pone.0047209

Abstract

BackgroundSepsis is a multifactorial pathology with high susceptibility to secondary infections. Innate and adaptive immunity are affected in sepsis, including monocyte deactivation.Methodology/Principal FindingsTo better understand the effects of alterations in monocytes on the regulation of immune responses during sepsis, we analyzed their differentiation in dendritic cell (DC). Cells from septic patients differentiated overwhelmingly into CD1a−negative DC, a population that was only a minor subset in controls and that is so far poorly characterized. Analysis of T cell responses induced with purified CD1a−negative and CD1a+ DC indicated that (i) CD1a−negative DC from both healthy individuals and septic patients fail to induce T cell proliferation, (ii) TGFβ and IL-4 were strongly produced in mixed leukocyte reaction (MLR) with control CD1a−negative DC; reduced levels were produced with patients DC together with a slight induction of IFNγ, (iii) compared to controls, CD1a+ DC derived from septic patients induced 3-fold more Foxp3+ T cells.Conclusion/SignificanceOur results indicate a strong shift in DC populations derived from septic patients’ monocytes with expanded cell subsets that induce either T cell anergy or proliferation of T cells with regulatory potential. Lower regulatory cytokines induction on a per cell basis by CD1a−negative dendritic cells from patients points however to a down regulation of immune suppressive abilities in these cells.

Highlights

Sepsis combines an acute infection with a systemic inflammatory response syndrome, and tends to have a better prognosis due to adapted resuscitation and management measures during the first 24 hours [1]
To investigate the mechanisms through which sepsis-induced immunodepression may contribute to susceptibility to infection, we examined the functions of dendritic cell (DC) derived from monocyte precursors in patients
We showed that circulating monocyte from peritonitis patients differentiated into CD1a2negative DC in a much larger proportion than control monocytes

Summary

Introduction

Sepsis combines an acute infection with a systemic inflammatory response syndrome, and tends to have a better prognosis due to adapted resuscitation and management measures during the first 24 hours [1]. Among the factors facilitating secondary infection, immune depression induced after a first insult, including sepsis, is increasingly incriminated [8,9,10]. Alterations in both innate and adaptive immune responses have been described in sepsis, the cellular and molecular mechanisms leading to increased susceptibility to secondary infections in patients have not been delineated. Analysis of innate immune responses and determining how they impact on adaptive responses in sepsis is needed to identify mechanisms that contribute to immunodepression. Several factors have been linked to immunodepression in animal models of sepsis such as inflammatory status and myeloid cell dysfunctions [11,12,13]. Innate and adaptive immunity are affected in sepsis, including monocyte deactivation

Methods

Results

Conclusion