Platelet factor 4 limits Th17 differentiation and cardiac allograft rejection

Abstract

Th cells are the major effector cells in transplant rejection and can be divided into Th1, Th2, Th17, and Treg subsets. Th differentiation is controlled by transcription factor expression, which is driven by positive and negative cytokine and chemokine stimuli at the time of T cell activation. Here we discovered that chemokine platelet factor 4 (PF4) is a negative regulator of Th17 differentiation. PF4-deficient and platelet-deficient mice had exaggerated immune responses to cardiac transplantation, including increased numbers of infiltrating Th17 cells and increased plasma IL-17. Although PF4 has been described as a platelet-specific molecule, we found that activated T cells also express PF4. Furthermore, bone marrow transplantation experiments revealed that T cell-derived PF4 contributes to a restriction in Th17 differentiation. Taken together, the results of this study demonstrate that PF4 is a key regulator of Th cell development that is necessary to limit Th17 differentiation. These data likely will impact our understanding of platelet-dependent regulation of T cell development, which is important in many diseases, in addition to transplantation.

An unexpected role for platelets in blocking Th17 differentiation

“…Histological examination of rejected grafts from Pf4 -/-mice revealed an atypical vasculopathy, with perivascular aggregates composed of T cells and dense infiltrates of neutrophils. Similar neutrophil recruitment after transplantation has been previously observed in Tbx21 -/-mice, also had an increased propensity for Th17 responses after transplantation (8). Recent studies in patients with autoimmune conditions associated with reduced numbers of platelets (and, presumably, PF4) also exhibit increased Th17 cell frequencies (13,14).…”

“…In this murine model of cardiac transplant, graft rejection is usually mediated by classical Th1-type responses, where CD4 + T cell effectors produce cytokines such as IFN-γ, IL-2, and GM-CSF (9). Although Th1 differentiation was disabled in Pf4 -/-hosts, Morrell and colleagues surprisingly found that grafts in these mice were rejected at an earlier time point compared with control animals (8). Histological examination of rejected grafts from Pf4 -/-mice revealed an atypical vasculopathy, with perivascular aggregates composed of T cells and dense infiltrates of neutrophils.…”

“…In this issue of the JCI, Shi, Morrell, and colleagues examined how platelets and platelet-derived PF4 affect anti-donor T cell responses after transplantation (8). Based on the broad premise that platelets and PF4 induce a proinflammatory response, the authors hypothesized that deletion of Pf4 in host mice would protect MHC class II-mismatched cardiac allografts from rejection.…”

The platelet P2 receptors in inflammation

“…Moreover, they interact with activated endothelium, undergo chemotaxis,"prime" leukocytes for efficient tissue recruitment, activate other inflammatory cells, exert phagocytosis, release biologically active substances, including adhesive proteins, vasoactive and proinflammatory mediators (1)(2)(3)(4)(5). Major platelet-derived chemokines and cytokines include PF4/CXCL4, pro-platelet basic protein (ppbp), RANTES, inorganic polyphosphate and IL-1β, among a large number of inflammatory molecules (6)(7)(8). Platelet-derived microparticles also contribute to the inflammatory process (9,10).…”

Platelets as immune-sensing cells

“…34 On the other hand, PF4 was found to be a negative regulator of Th17 differentiation, thereby limiting cardiac allograft rejection in a murine cardiac transplant model. 35 Platelets also release microparticles, which are small extracellular vesicles (the majority are ;200 nm in diameter) produced via blebbing and fission of the plasma membrane. Although several cells can produce microparticles, platelets appear to be highly effective in their production compared with other cell types.…”