Platelets are abundant, anucleated cells that mediate multiple functions, the most readily recognized of which is coagulation and hemostasis. It is now clear that activated platelets modulate local inflammatory responses including contact sensitivity, inflammatory bowel disease, and atherosclerosis through the interaction of platelet-derived ligands with endothelial cells and infiltrating leukocytes. Also, platelets express CD154 (CD40L), which is an important ligand for modulating adaptive immunity. To determine whether platelet-derived CD154 also modulated adaptive immunity, studies were initiated to characterize the effect of CD154 on T and B cell responses. A clear understanding of the platelet-derived signals necessary for optimal induction of adaptive immunity is important to understanding early events in immune activation. Data recently reported by our group demonstrate that platelet-derived CD154 is important for the development of adaptive immunity. The data demonstrate that activated platelets induce dendritic cell maturation and B cell isotype switching, and enhance CD8 +T cell responses. Importantly, platelet-derived CD154 alone was sufficient for the induction of isotype switching by B cells and augmentation of T lymphocyte antiviral responses. Furthermore, normal mice depleted of platelets prior to adenovirus injection exhibit decreased production of adenovirus-specific IgG, underscoring the importance of platelets in the generation of an optimal adaptive immune response. We hypothesize that platelet-derived CD154 is an early signal from the innate immune compartment that is necessary for optimal development of adaptive immunity. To test the hypothesis, studies are outlined to assess the effect of platelet-derived CD154 on B cell activation and antibody production.
The specific aims are as follows: (1) Characterize platelet-derived CD154 modulation of B cell activation. Using transfusion of platelets into CD154 negative mice, the identification of the B cell subsets stimulated by platelet-derived CD154 will be determined and the means by which platelets deliver the CD154 signal (intact platelets, platelet microparticles, or soluble CD154) will be tested. (2) Function of platelets in optimizing antibody production in cooperation with normal T cell function. These studies will assess the effect of platelet depletion on adaptive immunity. (3) Impact of continuous availability of platelet-derived CD 154 on antibody responses. These studies will use bone marrow chimeras to provide platelet-derived CD 154. In addition, the development of genetically modified mice in which megakaryocyte specific promoters are used to localize CD154 expression to platelets will be used to characterize the function of platelet-derived CD154 on adaptive immunity.
| Crist, Scott A; Sprague, Daniel L; Ratliff, Timothy L (2008) Nuclear factor of activated T cells (NFAT) mediates CD154 expression in megakaryocytes. Blood 111:3553-61 |
| Sprague, Daniel L; Sowa, Jennifer M; Elzey, Bennett D et al. (2007) The role of platelet CD154 in the modulation in adaptive immunity. Immunol Res 39:185-93 |
| Elzey, Bennett D; Sprague, Daniel L; Ratliff, Timothy L (2005) The emerging role of platelets in adaptive immunity. Cell Immunol 238:1-9 |
| Elzey, Bennett D; Grant, Julieann F; Sinn, Haley W et al. (2005) Cooperation between platelet-derived CD154 and CD4+ T cells for enhanced germinal center formation. J Leukoc Biol 78:80-4 |
| Crist, Scott A; Elzey, Bennett D; Ludwig, Aaron T et al. (2004) Expression of TNF-related apoptosis-inducing ligand (TRAIL) in megakaryocytes and platelets. Exp Hematol 32:1073-81 |
