Platelets are most recognized for their vital role as the cellular mediator of thrombosis, but platelets also have important immune functions. Platelets initiate and sustain vascular inflammation in many disease conditions, including arthritis, atherosclerosis, transplant rejection, and severe malaria. We now demonstrate that platelets express T cell costimulatory molecules, process and present Ag in MHC class I, and directly activate naive T cells in a platelet MHC class I-dependent manner. Using an experimental cerebral malaria mouse model, we also demonstrate that platelets present pathogen-derived Ag to promote T cell responses in vivo, and that platelets can be used in a cell-based vaccine model to induce protective immune responses. Our study demonstrates a novel Ag presentation role for platelets.

Summary Cerebral malaria is a major complication of Plasmodium falciparum infection in children. The pathogenesis of cerebral malaria involves vascular inflammation, immune stimulation and obstruction of cerebral capillaries. Platelets have a prominent role in both immune responses and vascular obstruction. We now demonstrate that the platelet derived chemokine, platelet factor 4 (PF4)/CXCL4, promotes the development of experimental cerebral malaria. Plasmodium infected red blood cells (RBC) activated platelets independent of vascular effects, resulting in increased plasma PF4. PF4 or CXCR3 null mice had less ECM, decreased brain T-cell recruitment, and platelet depletion or aspirin treatment reduced the development of ECM. We conclude that Plasmodium infected RBC can activate platelets and platelet derived PF4 then contributes to immune activation and T-cell trafficking as part of the pathogenesis of ECM.

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.

Platelets are most recognized as the cellular mediator of thrombosis, but they are increasingly appreciated for their immunomodulatory roles, including responses to Plasmodium infection. Platelet interactions with endothelial cells and leukocytes contribute significantly to the pathogenesis of experimental cerebral malaria (ECM). Recently it has been suggested that platelets not only have an adverse role in cerebral malaria, but platelets may also be protective in animal models of uncomplicated malaria. We now demonstrate that these diverse and seemingly contradictory roles for platelets extend to cerebral malaria models and are dependent on the timing of platelet activation during infection. Our data shows that platelets are activated very early in ECM and have a central role in initiation of the acute phase response to blood stage infection. Unlike platelet depletion or inhibition post infection, pre-infection platelet depletion or treatment with a platelet inhibitor is not protective. Additionally, we show that platelet driven acute phase responses have a major role in protecting mice from ECM by limiting parasite growth. Our data now suggests that platelets have a complex role in ECM pathogenesis: platelets help limit parasite growth early post infection, but with continued platelet activation as the disease progresses, platelets contribute to ECM associated inflammation.