Inhibition of Dendritic Cell Activation and Modulation of T Cell Polarization by the Platelet Secretome.

Anno Saris,S Marieke Van Ham,Juulke Steuten,Anja Ten Brinke,Gijs Van Schijndel,David P Schrijver,Jaap Jan Zwaginga

doi:10.3389/fimmu.2021.631285

Abstract

Platelet transfusions are a frequently administered therapy for especially hemato-oncological patients with thrombocytopenia. Next to their primary function in hemostasis, currently there is increased attention for the capacity of platelets to affect the function of various cells of the immune system. Here, we investigate the capacity of platelets to immuno-modulate monocyte-derived dendritic cells (moDC) as well as primary dendritic cells and effects on subsequent T cell responses. Platelets significantly inhibited pro-inflammatory (IL-12, IL-6, TNFα) and increased anti-inflammatory (IL-10) cytokine production of moDCs primed with toll-like receptor (TLR)-dependent and TLR-independent stimuli. Transwell assays and ultracentrifugation revealed that a soluble factor secreted by platelets, but not microvesicles, inhibited DC activation. Interestingly, platelet-derived soluble mediators also inhibited cytokine production by human ex vivo stimulated myeloid CD1c+ conventional DC2. Moreover, platelets and platelet-derived soluble mediators inhibited T cell priming and T helper differentiation toward an IFNγ+ Th1 phenotype by moDCs. Overall, these results show that platelets are able to inhibit the pro-inflammatory properties of DCs, and may even induce an anti-inflammatory DC phenotype, with decreased T cell priming capacity by the DC. The results of this study provide more insight in the potential role of platelets in immune modulation, especially in the context of platelet transfusions.

Highlights

Up to three million platelet transfusions are administered every year in Europe, and the majority of these transfusions are administered to hemato-oncological patients [1,2,3,4,5,6,7]
Our studies revealed that upon activation platelets release soluble factors that affect both monocyte-derived DCs (moDCs) and primary myeloid CD1c+ conventional DC2 cytokine production induced by a range of toll-like receptors (TLRs)-dependent and TLR-independent stimuli with minimal effects on co-stimulatory marker expression
To investigate if and to what extent platelets affect human Dendritic cells (DCs) function, monocyte-derived DCs were stimulated with several stimuli to mimic various types of physiological activation, including monophosporyl lipid A (MPLA) (TLR4; Figure 1A), PAM3CSK4 (TLR1/2; Figure 1C), R848 (TLR7/8; Figure 1D) or flagellin (TLR5; Figure 1E) in the presence of IFNg or with a cytokine maturation cocktail containing IL-1b, TNF-a; and prostaglandin E2 (PGE2) (Figure 1B, TNF-a not measured as this was added with stimulation cocktail)

Summary

Introduction

Up to three million platelet transfusions are administered every year in Europe, and the majority (up to 65%) of these transfusions are administered to hemato-oncological patients [1,2,3,4,5,6,7]. Prophylactic administration of platelet transfusions in patients not at direct risk of bleeding is currently subject of debate [6,7,8,9]. TRIM associates with increased risk of infections, decreased graft rejection and recurrence of tumor growth in patients receiving transfusions [14,15,16]. Platelet derived active transforming growth factor b (TGF-b), together with lactate, was found to inhibit T cell anti-tumor functions [29]. Due to increased understanding of the potential immune functions of platelets, the question arises to what extent transfused platelets will affect the recipient’s immune system [12, 17, 20, 30, 31], which would be especially relevant for hematological patients that are frequently strongly immunecompromised [7]

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