TY - JOUR
T1 - Platelet microparticles inhibit IL-17 production by regulatory T cells through P-selectin
AU - Dinkla, Sip
AU - Van Cranenbroek, Bram
AU - Van Der Heijden, Wouter A.
AU - He, Xuehui
AU - Wallbrecher, Rike
AU - Dumitriu, Ingrid
AU - Van Der Ven, Andre
AU - Bosman, Giel
AU - Koenen, Hans
AU - Joosten, Irma
PY - 2016/4/21
Y1 - 2016/4/21
N2 - Self-tolerance and immune homeostasis are orchestrated by FOXP3+ regulatory T cells (Tregs). Recent data have revealed that upon stimulation, Tregs may exhibit plasticity toward a proinflammatory phenotype, producing interleukin 17 (IL-17) and/or interferon γ (IFN-γ). Such deregulation of Tregs may contribute to the perpetuation of inflammatory processes, including graft-versus-host disease. Thus, it is important to identify immunomodulatory factors influencing Treg stability. Platelet-derived microparticles (PMPs) are involved in hemostasis and vascular health and have recently been shown to be intimately involved in (pathogenic) immune responses. Therefore, we investigated whether PMPs have the ability to affect Treg plasticity. PMPs were cocultured with healthy donor peripheral blood–derived Tregs that were stimulated with anti-CD3/CD28 monoclonal antibodies in the presence of IL-2, IL-15, and IL-1β. PMPs prevented the differentiation of peripheral blood–derived Tregs into IL-17– and IFN-γ–producing cells, even in the presence of the IL-17–driving proinflammatory cytokine IL-1β. The mechanism of action by which PMPs prevent Treg plasticity consisted of rapid and selective P-selectin–dependent binding of PMPs to a CCR6+HLA-DR+ memory-like Treg subset and their ability to inhibit Treg proliferation, in part through CXCR3 engagement. The findings that ∼8% of Tregs in the circulation of healthy individuals are CD41+P-selectin+ and that distinct binding of patient plasma PMPs to Tregs was observed support in vivo relevance. These findings open the exciting possibility that PMPs actively regulate the immune response at sites of (vascular) inflammation, where they are known to accumulate and interact with leukocytes, consolidating the (vascular) healing process.
AB - Self-tolerance and immune homeostasis are orchestrated by FOXP3+ regulatory T cells (Tregs). Recent data have revealed that upon stimulation, Tregs may exhibit plasticity toward a proinflammatory phenotype, producing interleukin 17 (IL-17) and/or interferon γ (IFN-γ). Such deregulation of Tregs may contribute to the perpetuation of inflammatory processes, including graft-versus-host disease. Thus, it is important to identify immunomodulatory factors influencing Treg stability. Platelet-derived microparticles (PMPs) are involved in hemostasis and vascular health and have recently been shown to be intimately involved in (pathogenic) immune responses. Therefore, we investigated whether PMPs have the ability to affect Treg plasticity. PMPs were cocultured with healthy donor peripheral blood–derived Tregs that were stimulated with anti-CD3/CD28 monoclonal antibodies in the presence of IL-2, IL-15, and IL-1β. PMPs prevented the differentiation of peripheral blood–derived Tregs into IL-17– and IFN-γ–producing cells, even in the presence of the IL-17–driving proinflammatory cytokine IL-1β. The mechanism of action by which PMPs prevent Treg plasticity consisted of rapid and selective P-selectin–dependent binding of PMPs to a CCR6+HLA-DR+ memory-like Treg subset and their ability to inhibit Treg proliferation, in part through CXCR3 engagement. The findings that ∼8% of Tregs in the circulation of healthy individuals are CD41+P-selectin+ and that distinct binding of patient plasma PMPs to Tregs was observed support in vivo relevance. These findings open the exciting possibility that PMPs actively regulate the immune response at sites of (vascular) inflammation, where they are known to accumulate and interact with leukocytes, consolidating the (vascular) healing process.
U2 - 10.1182/blood-2015-04-640300
DO - 10.1182/blood-2015-04-640300
M3 - Article
SN - 0006-4971
VL - 127
SP - 1976
EP - 1986
JO - Blood
JF - Blood
IS - 16
ER -