Platelet-Derived Ectosomes Reduce NK Cell Function

Abstract

Platelet (PLT) transfusions are potentially life saving for individuals with low PLT numbers; however, previous work revealed that PLT transfusions are associated with increased infection risk. During storage, PLT intended for transfusion continuously shed ectosomes (Ecto) from their surface, which express immunomodulatory molecules like phosphatidylserine or TGF-β1. Recently, PLT-Ecto were shown to reduce proinflammatory cytokine release by macrophages and to favor the differentiation of naive T cells toward regulatory T cells. Whether PLT-Ecto modify NK cells remains unclear. We exposed purified NK cells and full PBMCs from healthy donors to PLT-Ecto. We found a reduced expression of several activating surface receptors (NKG2D, NKp30, and DNAM-1) and decreased NK cell function, as measured by CD107a expression and IFN-γ production. Pretreatment of PLT-Ecto with anti–TGF-β1 neutralizing Ab restored surface receptor expression and NK cell function. We further observed a TGF-β1–mediated upregulation of miR-183, which, in turn, reduced DAP12, an important protein for stabilization and downstream signaling of several activating NK cell receptors. Again, these effects could antagonized, in part, when PLT-Ecto were preincubated with anti–TGF-β1 Ab. Erythrocyte Ecto did not affect NK cells. Polymorphonuclear cell Ecto expressed MHC class I and inhibited NK cell function. In addition, they induced the secretion of TGF-β1 by NK cells, which participated in an auto/paracrine manner in the suppressive activity of polymorphonuclear cell–derived Ecto. In sum, our study showed that PLT-Ecto could inhibit NK cell effector function in a TGF-β1–dependent manner, suggesting that recipients of PLT transfusions may experience reduced NK cell function.

New insights into cancer's exploitation of platelets

“…TGF‐β1 downregulates expression of activating NK cell receptors (ie, NKG2D and CD16) as well as multiple cytokine mediators/enzymes, resulting in diminished NK cell‐killing capacity . Consistent with the view that platelet‐derived TGF‐β1 promotes metastasis by limiting NK cell functions, previous studies have shown that platelet‐specific deletion of TGF‐β1 significantly limits metastatic potential . One straightforward hypothesis that could couple the observations of Lucotti et al with these previous findings is that TXA 2 is critical to support platelet‐mediated secretion of TGF‐β1 from α granules.…”

“…22,23 Consistent with the view that platelet-derived TGF-β1 promotes metastasis by limiting NK cell functions, previous studies have shown that platelet-specific deletion of TGF-β1 significantly limits metastatic potential. 19,24 One straightforward hypothesis that could couple the observations of Lucotti et al with these previous findings is that TXA 2 is critical to support platelet-mediated secretion of TGF-β1 from α granules. Alternatively, studies in which the TXA 2 pathway is targeted in the context of platelets lacking TGF-β1 could also reveal novel mechanisms coupling TXA 2 -mediated platelet functions to metastasis independent of TGF-β1 secretion.…”

“…Using fluorescently-labeled monocytes and macrophages, this study found that COX-1 (but not COX-2) and TXA 2 signaling inhibition Previous studies showed that platelets promote metastasis through a mechanism that involves impedance of natural killer (NK) cell-mediated clearance of micrometastases. [15][16][17][18][19] While the mechanisms by which platelets impede NK-mediated clearance of newly adherent metastatic tumor cells in the lungs remain an active area of study, it is notable that previous studies demonstrated that in the absence of functioning NK cells, platelet function was no longer a determinant of early tumor cell survival. 17 Notably, the timeframe whereby platelet/NK cell interactions impacted metastatic potential closely paralleled that observed for the COX-1/TXA 2 pathway.…”

“…While the elegant studies by Lucotti et al shed significant light on the specific role of the platelet COX‐1/TXA 2 pathway in metastasis, these studies also raise interesting and important questions. Previous studies showed that platelets promote metastasis through a mechanism that involves impedance of natural killer (NK) cell‐mediated clearance of micrometastases . While the mechanisms by which platelets impede NK‐mediated clearance of newly adherent metastatic tumor cells in the lungs remain an active area of study, it is notable that previous studies demonstrated that in the absence of functioning NK cells, platelet function was no longer a determinant of early tumor cell survival .…”

Mechanisms of red blood cell transfusion‐related immunomodulation

“…While less is known about PLT‐derived factors as TRIM mediators, emerging data strongly suggest that PLTs and PLT‐derived factors have important immunomodulatory potential . For instance, PLT‐derived microparticles are capable of inducing both immune cell suppression and activation . PLTs themselves may play important roles in modulating immune cell response in both health and disease, suggesting that residual PLTs found in RBC products likely contribute to immunomodulation.…”