Our results demonstrate that platelets present antigen to T cells in a platelet MHCI dependent manner and that platelets acquire and present Plasmodium derived antigen to CD8+ T cells both in vitro and in vivo. This represents an important new concept; platelets not only support and promote acquired immune responses, but platelets may also directly participate in the initiation of acquired immune responses. A platelet antigen presentation role may be important in many blood borne infections and vascular inflammatory diseases. Thrombocytopenia and inflammation are associated with malaria, dengue and HIV amongst other infectious diseases. Immune mediated thrombocytopenia (ITP) can also be the result of cytoxic T cell responses to platelets presenting self antigen. The pathogenesis of infection related thrombocytopenias and ITP are likely multiple, but may in part be driven by platelets presenting antigen and being specifically targeted by CD8+ T cells.
Initiation of innate and acquired immune responses by platelets is a potentially important mechanism to combat infectious agents. Following a breach in the skin for example, platelets limit bleeding, but they also simultaneously recruit and activate ‘professional’ immune cells to limit skin pathogen dissemination. Platelet presentation of foreign antigen derived from the site of the skin lesion may provide an early means to respond to subsequent antigen exposure. Because platelets are much more numerous than leukocytes and tissue restricted professional antigen presenting cells, an antigen presentation function may also provide early blood surveillance to begin antigen specific responses before more specialized cells become involved. Platelets can be activated by and phagocytose bacteria, and can be infected by numerous types of viruses, perhaps indicating a more active role in antigen presentation than previously considered. There is also growing evidence that platelets may traffic in a regulated manner. Platelets can access lymph nodes and appear to have the ability to undergo regulated diapedesis supporting our evidence that they may have specific T cell interactions (54
It has been suggested that more platelet MHCI is absorbed from the plasma than is derived from the platelet itself (56
). Our results indicate that platelets express significant amounts of MHCI and that during infection a population of platelets emerges that express greatly increased MHCI. MHC peptide loading takes place in the endoplasmic reticulum (ER) and traffics through the Golgi to the membrane surface via a secretory pathway. As noted above, platelets have an ER and Golgi (11
) as well as other components necessary for MHCI peptide loading including TAP, calnexin, calreticulin, and ERp57 (12
), further supporting the concept that platelets process antigen and regulate MHCI expression. Platelet mRNA expression data has shown that compared to other transcripts, platelets have large amounts of antigen presentation related mRNA, in particular β2M and HLA mRNA are highly abundant in platelets (15
). Our data, the high mRNA expression, and ability of platelets to upregulate protein expression in the periphery (57
) may further indicate the importance of regulating MHCI expression and antigen presentation in platelets. Whether platelets present antigen as a result of platelet infection, or whether platelets present antigen they have taken up by phagocytosis is unclear from our studies and requires much further work to clarify.
Because dendritic cells (DC) induce robust T cell responses, cell-based vaccine research has focused on DCs, with cancer and HIV the diseases most often targeted. Mature DCs provide optimal immune stimulation, but immature DCs may tolerize T cells. This means that DCs need to be significantly manipulated in culture prior to in vivo
use. On an individual cell basis, platelets may not induce as robust an immune response as professional antigen presenting cells, and platelets are limited by their expression of only MHC class I. But platelets may offer many other unique advantages for cell based vaccine development, including platelets are easy to isolate in large numbers and do not require extensive manipulation and differentiation. Much further study is needed to determine whether platelets can be effective in presenting Plasmodium
restricted antigens for vaccine development, but our data does demonstrate the ability of platelets presenting antigen to induce T cell activation in vivo
. The ‘WT platelet/OVA vaccine’ treated mice eventually developed an increasing parasite burden after about day 15 post-infection indicating that the mice were protected from the ECM phase, but the parasite eventually escapes the protection offered by the platelet vaccine. CM protection is an important therapeutic goal and these results point out the complexity of malaria immune responses and disease pathogenesis. Our data also demonstrates that although CD8+
T cells are deleterious in the late stages of ECM and drive ECM pathogenesis (51
), an early, robust CD8 response can be protective. Although our data represents an important novel proof of principle, there is of course much work that must be done to better understand the long-term therapeutic potential of our results, and any potential adverse side effects. Because platelets are pro-inflammatory and the cellular mediator of thrombosis unintended side effects must also be given great study and consideration.
Platelets are dynamic cells and represent an early link between the innate and acquired immune responses in many vascular inflammatory processes, including cerebral malaria. Thrombosis and vascular inflammation represent a continuum of each other; platelet activation incites an immune response and vascular inflammation leads to platelet activation. Our data extends this important paradigm to platelet antigen presentation in the context of MHCI.