Background CXCL4 is a chemokine produced by activated platelets and immune cells. Several studies have reported that CXCL4 plays a critical role on physiological processes since it affects the proliferation and maturation of megakaryocytic and hematopoietic progenitor cells, regulates coagulation and wound healing, displays anti-tumoral and angiostatic activity and induces immune cell modulation. Dysregulation of these processes causes the disturbance of the immune system and homeostasis, and might lead to pathological conditions. Indeed, a strong correlation was previously found between elevated CXCL4 levels in the circulation and the clinical features of patients with systemic sclerosis (SSc) (1). Dendritic cells are essential players in innate defence and bridging towards adaptive immune responses, thereby contributing to both immune activation and maintenance of homeostasis.
Objectives Considering previous observations on the association of dendritic cells and T-cell dysfunction in SSc, we here investigated the effect of CXCL4 on monocyte-derived DC (moDC) differentiation, on Toll-like receptor (TLR)-mediated responses and on activation of polyclonal and antigen-specific CD8+T-cells.
Methods To this end, we compared the phenotype, TLR-mediated responses and CD8+T-cell activation by moDCs and CXCL4 exposed moDCs.
Results Already prior to TLR stimulation, CXCL4-moDCs displayed a more matured phenotype. We found that CXCL4 exposure can sensitize moDCs for TLR-ligand responsiveness, as illustrated by a dramatic upregulation of CD83, CD86 and MHC class I, and markedly increased secretion of IL-12 and TNF-α in response to TLR3 and TLR7/8-agonists. Next, we analyzed the effect of CXCL4 in modulating DC-mediated CD8+ T-cell activation. CXCL4-moDCs strongly potentiated proliferation of polyclonal CD8+ T-cells and production of interferon (IFN)-γ and IL-4, in an antigen-independent manner. While the internalization of antigen was comparable to moDCs, antigen processing by CXCL4-moDCs was impaired. Yet, these cells were more potent at stimulating antigen-specific CD8+ T-cell responses.
Conclusions Together our data supports that increased levels of circulating CXCL4 may contribute to immune dysregulation through the modulation of innate and adaptive responses by dendritic cells.
Van Bon, L & Affandi, A J; et al. 2014. Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N. Engl. J. Med. 370: 433–43.
Acknowledgements Supported by a PhD grant from the Portuguese Fundação para a Ciência e a Tecnologia (SFRH/BD/89643/2012) to S.C.S.C.; A.J.A. was supported by the grants from the Dutch Arthritis Association (Reumafonds grant NR-10–1-301) and the Netherlands Organization for Science Research (Mosaic grant 017.008.014); T.R.D.J.R. was funded by an ERC Starting grant, a grant from the Dutch Arthritis Foundation and Pre-Seed grant Dutch Association of Science (NWO).
Disclosure of Interest None declared
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