Presenting the Antigen-Presenting Platelet

The role of platelets in mediating inflammatory processes is becoming increasingly recognized.¹  Most of the studies in this area have centered on the interaction of platelets with monocytes and neutrophils, but now Chapman et al., in the laboratory of Craig Morrell at the University of Rochester, provide evidence that platelets activate T cells in an MHC class I-dependent manner. MHC class I molecules are α/β2-microglobulin heterodimers that are found on the surface of all nucleated cells. During synthesis and transport through the endoplasmic reticulum and Golgi, MHC class I molecules bind to peptides that have been processed from either host or foreign intracellular proteins. At the cell surface, MHC class I molecules present these peptide antigens to T-cell receptors (TCRs). In contrast, MHC class II molecules are found only on so-called “professional” antigen-presenting cells (dendritic cells, macrophages, and B cells). Peptide-loading onto MHC class II molecules occurs following proteolysis of internalized extracellular proteins. Following engagement of antigen–MHC class I or II molecules by the TCR to produce so-called “signal 1,” a second signal is required for T-cell activation. This process, called co-stimulation, involves engagement of T-cell molecules CD40L and CD28 with antigen-presenting cell receptors CD40 and CD80/86.

Although platelets had not been previously associated with processing or presenting Ag, the authors noted that many of the components required for antigen presentation, including proteasomes and mRNAs for MHC class I subunits, had been identified in platelets.²  Using flow cytometry, they found that murine and human platelets express MHC class I molecules and CD40. Human, but not murine, platelets also expressed CD86. In contrast, MHC class II expression was not detected. Next they studied T-cell activation by measuring IL-2 production or CD69 expression. Murine T cells stimulated with an antibody to the TCR co-receptor CD3 to provide signal 1 were not activated. However, the addition of platelets to provide co-stimulation resulted in activation. Murine platelets incubated with intact ovalbumin (OVA) subsequently bound antibody specific for MHC class I–OVA peptide complex, indicating that platelets process and present antigen. Platelets from OVA transgenic (OVA-Tg) mice were used in additional studies. These mice present MHC I–OVA peptides on the surface of all MHC I-positive cells, including platelets. When incubated with OVA-Tg platelets, T cells from transgenic mice bearing TCRs that recognize OVA (OT-1 mice) were activated, as judged by increased production of IL-2 and interferon γ, but T cells from wild-type mice were not activated by OVA-Tg platelets. In addition, injection of OVA-Tg platelets into OT-1 mice resulted in increased in vivo production of IL-2 compared with wild-type mice.

The authors then explored the role of platelet MHC class I-dependent events in a model of cerebral malaria produced by infection of mice with Plasmodium berghei. Production of thrombocytopenia using an anti-platelet antibody resulted in decreased production of plasma IL-2 and interferon γ compared with non-thrombocytopenic controls. Additionally, platelet MHC class I expression was increased in mice infected with P. berghei. Mice also were infected with a transgenic variant of P. berghei that expresses an OVA peptide. Infected red cells from these mice were incubated with OT-1 T cells and with platelets from either wild-type or MHC class I-deficient mice. T-cell activation was observed with wild-type platelets, indicating that platelets can process and present parasitederived antigen to T cells in an MHC class I-dependent manner.

Finally, the authors used the transgenic variant of P. berghei to explore a cell-based vaccine strategy for prevention of malaria. Platelets from wild-type or MHC class I-deficient mice were incubated with an OVA peptide and then injected intravenously into wild-type mice on days one and 10. The mice were then challenged with a lethal dose of P. berghei on day 21. There was a significant increase in survival of mice immunized with wild-type platelets compared with MHC class I-deficient platelets. Additionally, the mice immunized with OVA-treated, wild-type platelets showed both decreased parasitemia and increased OVA-specific cytotoxic (CD8⁺) T cells.