While platelets are the cellular mediators of thrombosis, platelets are also immune cells. Platelets interact both directly and indirectly with immune cells, impacting their activation and differentiation, as well as all phases of the immune response. Megakaryocytes (Mks) are the cell source of circulating platelets, and until recently Mks were typically only considered as bone marrow (BM) resident cells. However, platelet producing Mks also reside in the lung, and lung Mks express greater levels of immune molecules compared to BM Mks. We therefore sought to define the immune functions of lung Mks. Using single cell RNA-Seq of BM and lung myeloid enriched cells, we found that lung Mks (MkL) had gene expression patterns that are similar to antigen presenting cells (APC). This was confirmed using imaging and conventional flow cytometry. The immune phenotype of Mks was plastic and driven by the tissue immune environment as evidenced by BM Mks having a MkL like phenotype under the influence of pathogen receptor challenge and lung associated immune molecules, such as IL-33. Our in vitro and in vivo assays demonstrated that MkL internalized and processed both antigenic proteins and bacterial pathogens. Furthermore, MkL induced CD4 + T cell activation in a MHC II dependent manner both in vitro and in vivo. These data indicated that Mks in the lung had key immune regulatory roles dictated in part by the tissue environment.

Classically, platelets have been described as the cellular blood component that mediates hemostasis and thrombosis. This important platelet function has received significant research attention for >150 years. The immune cell functions of platelets are much less appreciated. Platelets interact with and activate cells of all branches of immunity in response to pathogen exposures and infection, as well as in response to sterile tissue injury. In this review, we focus on innate immune mechanisms of platelet activation, platelet interactions with innate immune cells, as well as the intersection of platelets and adaptive immunity. The immune potential of platelets is dependent in part on their megakaryocyte precursor providing them with the molecular composition to be first responders and immune sentinels in initiating and orchestrating coordinated pathogen immune responses. There is emerging evidence that extramedullary megakaryocytes may be immune differentiated compared with bone marrow megakaryocytes, but the physiological relevance of immunophenotypic differences are just beginning to be explored. These concepts are also discussed in this review. The immune functions of the megakaryocyte/platelet lineage have likely evolved to coordinate the need to repair a vascular breach with the simultaneous need to induce an immune response that may limit pathogen invasion once the blood is exposed to an external environment.

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The malaria causing Plasmodium parasite is a major public health threat. Plasmodium vivax (P vivax) is the cause of uncomplicated malaria (UCM). Platelets are the cellular mediators of thrombosis and are also the most numerous immune cells in the blood, and a first responder to infections. Thrombocytopenia is a frequent complication of malaria, and a decrease in platelet count is a negative predictor of disease outcome. Malaria infection elicits a strong interferon gamma (IFNγ) response. IFNγ is a potent inducer of indoleamine 2,3-dioxygenase (IDO1) the rate-limiting enzyme that catalyzes the first step in Tryptophan (Trp) metabolism in the kynurenine (Kyn) pathway, shunting Trp away from serotonin production. Trp metabolism may be altered in malaria infection as a means to regulate immunometabolic responses, but the mechanisms remain unknown. Our platelet RNA-sequencing data from P vivax infected humans and from P yoelii infected mice showed increased expression of genes related to Trp metabolism, including IDO1 . The role for platelets in metabolic pathway regulation is poorly explored in general, but particularly in infectious diseases. We introduce a novel idea that platelets participate in immunometabolism to infection. Using complementary experimental approaches such as liquid chromatography-mass spectrometry, ELISA, PCR, western blot, and flow cytometry, we test the hypothesis that platelets are a source of IDO1 in UCM malaria, and thrombocytopenia results in IDO1 depletion and immune dysregulation. We have discovered a role for platelets in Trp metabolic pathway regulation and that platelet regulated immune responses to malaria infection are in part dependent on the Trp metabolic pathways. During P yoelii infection there is a depletion of Trp, and increased Kyn metabolites, as well as decreased plasma serotonin. Platelet transfusions to infected mice can increase Kyn. Understanding the interplay between platelets and immunometabolic pathways may provide a better understanding of the impact of thrombocytopenia in diseases beyond malaria, and provide a means to improve malaria infection responses as well as improved platelet-directed therapeutics in many hematological, metabolic, and immune diseases .