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.
Synthetic cancer
vaccines may boost anticancer immune responses
by co-delivering tumor antigens and adjuvants to dendritic cells (DCs).
The accessibility of cancer vaccines to DCs and thereby the delivery
efficiency of antigenic material greatly depends on the vaccine platform
that is used. Three-dimensional scaffolds have been developed to deliver
antigens and adjuvants locally in an immunostimulatory environment
to DCs to enable sustained availability. However, current systems
have little control over the release profiles of the cargo that is
incorporated and are often characterized by an initial high-burst
release. Here, an alternative system is designed that co-delivers
antigens and adjuvants to DCs through cargo-loaded nanoparticles (NPs)
incorporated within biomaterial-based scaffolds. This creates a programmable
system with the potential for controlled delivery of their cargo to
DCs. Cargo-loaded poly(
d
,
l
-lactic-
co
-glycolic acid) NPs are entrapped within the polymer walls of alginate
cryogels with high efficiency while retaining the favorable physical
properties of cryogels, including syringe injection. DCs cultured
within these NP-loaded scaffolds acquire strong antigen-specific T
cell-activating capabilities. These findings demonstrate that introduction
of NPs into the walls of macroporous alginate cryogels creates a fully
synthetic immunostimulatory niche that stimulates DCs and evokes strong
antigen-specific T cell responses.
The generation of high-affinity antibodies requires an efficient germinal center (GC) response. As differentiating B cells cycle between GC dark and light zones they encounter different oxygen pressures (pO2). However, it is essentially unknown if and how variations in pO2 affect B cell differentiation, in particular for humans. Using optimized in vitro cultures together with in-depth assessment of B cell phenotype and signaling pathways, we show that oxygen is a critical regulator of human naive B cell differentiation and class switch recombination. Normoxia promotes differentiation into functional antibody secreting cells, while a population of CD27++ B cells was uniquely generated under hypoxia. Moreover, time-dependent transitions between hypoxic and normoxic pO2 during culture - reminiscent of in vivo GC cyclic re-entry - steer different human B cell differentiation trajectories and IgG class switch recombination. Taken together, we identified multiple mechanisms trough which oxygen pressure governs human B cell differentiation.
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