Serotonin (5-Hydroxytryptamine, 5-HT) plays an important role in many organs as a peripheral hormone. Most of the body's serotonin is circulating in the bloodstream, transported by blood platelets and is released upon activation. The functions of serotonin are mediated by members of the 7 known mammalian serotonin receptor subtype classes (15 known subtypes), the serotonin transporter (SERT) and by covalent binding of serotonin to different effector proteins. Almost all immune cells express at least one serotonin component. In recent years, a number of immunoregulatory functions have been ascribed to serotonin. In monocytes/macrophages for example serotonin modulates cytokine secretion. Serotonin can also suppress the release of TNF-α and IL-1β by activating serotonin receptors. Furthermore, neutrophil recruitment and T-Cell activation can both be mediated by serotonin. These are only a few of the known immunomodulatory roles of serotonin that we will review here.

Emerging data indicate that SARS-CoV-2-specific CD8⁺ T cells targeting different viral proteins are detectable in up to 70% of convalescent individuals^1,2,3,4,5. However, very little information is currently available about the abundance, phenotype, functional capacity and fate of pre-existing and induced SARS-CoV-2-specific CD8⁺ T cell responses during the natural course of SARS-CoV-2 infection. Here, we define a set of optimal and dominant SARS-CoV-2-specific CD8⁺ T cell epitopes. We also perform a high-resolution ex vivo analysis of pre-existing and induced SARS-CoV-2-specific CD8⁺ T cells, applying peptide-loaded major histocompatibility complex class I (pMHCI) tetramer technology. We observe rapid induction, prolonged contraction and emergence of heterogeneous and functionally competent cross-reactive and induced memory CD8⁺ T cell responses in cross-sectionally analyzed individuals with mild disease following SARS-CoV-2 infection and three individuals longitudinally assessed for their T cells pre- and post-SARS-CoV-2 infection. SARS-CoV-2-specific memory CD8⁺ T cells exhibited functional characteristics comparable to influenza-specific CD8⁺ T cells and were detectable in SARS-CoV-2 convalescent individuals who were seronegative for anti-SARS-CoV-2 antibodies targeting spike (S) and nucleoprotein (N). These results define cross-reactive and induced SARS-CoV-2-specific CD8⁺ T cell responses as potentially important determinants of immune protection in mild SARS-CoV-2 infection.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe adverse effect of ChAdOx1 nCoV-19 COVID-19 vaccine (Vaxzevria) and Janssen Ad26.COV2.S COVID-19 vaccine, and it is associated with unusual thrombosis. VITT is caused by anti-platelet factor 4 (PF4) antibodies activating platelets through their FcγRIIa receptors. Antibodies that activate platelets through FcγRIIa receptors have also been identified in patients with COVID-19. These findings raise concern that vaccination-induced antibodies against anti-SARS-CoV-2 spike protein cause thrombosis by cross-reacting with PF4. Immunogenic epitopes of PF4 and SARS-CoV-2 spike protein were compared using in silico prediction tools and 3D modeling. The SARS-CoV-2 spike protein and PF4 share at least 1 similar epitope. Reactivity of purified anti-PF4 antibodies from patients with VITT was tested against recombinant SARS-CoV-2 spike protein. However, none of the affinity-purified anti-PF4 antibodies from 14 patients with VITT cross-reacted with SARS-CoV-2 spike protein. Sera from 222 polymerase chain reaction–confirmed patients with COVID-19 from 5 European centers were tested by PF4-heparin enzyme-linked immunosorbent assays and PF4-dependent platelet activation assays. We found anti-PF4 antibodies in sera from 19 (8.6%) of 222 patients with COVID-19. However, only 4 showed weak to moderate platelet activation in the presence of PF4, and none of those patients developed thrombotic complications. Among 10 (4.5%) of 222 patients who had COVID-19 with thrombosis, none showed PF4-dependent platelet-activating antibodies. In conclusion, antibodies against PF4 induced by vaccination do not cross-react with the SARS-CoV-2 spike protein, indicating that the intended vaccine-induced immune response against SARS-CoV-2 spike protein is not the trigger of VITT. PF4-reactive antibodies found in patients with COVID-19 in this study were not associated with thrombotic complications.

Obstruction of a coronary artery causes ischemia of heart tissue leading to myocardial infarction. Prolonged oxygen deficiency provokes tissue necrosis, which can result in heart failure and death of the patient. Therefore, restoration of coronary blood flow (reperfusion of the ischemic area) by re-canalizing the affected vessel is essential for a better patient outcome. Paradoxically, sudden reperfusion also causes tissue injury, thereby increasing the initial ischemic damage despite restoration of blood flow (=ischemia/reperfusion injury, IRI). Myocardial IRI is a complex event that involves various harmful mechanisms (e.g., production of reactive oxygen species and local increase in calcium ions) as well as inflammatory cells and signals like chemokines and cytokines. An involvement of platelets in the inflammatory reaction associated with IRI was discovered several years ago, but the underlying mechanisms are not yet fully understood. This mini review focusses on platelet contributions to the intricate picture of myocardial IRI. We summarize how upregulation of platelet surface receptors and release of immunomodulatory mediators lead to aggravation of myocardial IRI and subsequent cardiac damage by different mechanisms such as recruitment and activation of immune cells or modification of the cardiac vascular endothelium. In addition, evidence for cardioprotective roles of distinct platelet factors during IRI will be discussed.

Summary: This review collects evidence about immune and inflammatory functions of platelets from a clinician’s point of view. A focus on clinically relevant immune functions aims at stimulating further research, because the complexity of platelet immunity is incompletely understood and not yet translated into patient care. Platelets promote chronic inflammatory reactions (e.g. in atherosclerosis), modulate acute inflammatory disorders such as sepsis and other infections (participating in the host defense against pathogens), and contribute to exacerbations of autoimmune conditions (like asthma or arthritis). It would hence be obsolete to restrict a description of platelet functions to thrombosis and haemostasis – platelets clearly are the most abundant cells with immune functions in the circulation.

Serotonin (5-Hydroxytryptamine, 5-HT) was discovered as a vasoconstrictor in 1937. Since its discovery, the involvement of serotonin in numerous physiological processes was described. It acts as an important neurotransmitter, regulates bowel movement, can be released as a tissue hormone and acts as a growth factor. Among the years, a link between serotonin and inflammation has been identified and further evidence suggests an important role of serotonergic components in immune responses. Peripheral serotonin is synthesized by the enzyme tryptophan hydroxylase (Tph), which exists in two different isoforms: Tph2 being responsible for serotonin synthesis in neurons and Tph1 for generation of serotonin in peripheral organs. After synthesis in intestinal enterochromaffin cells, serotonin is stored in platelets and released upon stimulation. Several immune cells express the serotonin transporter SERT and enzymes for serotonin metabolism (monoamine oxygenase, MAO). To be susceptible to changes in serotonin levels, serotonin receptors are required and almost all of the 15 receptor subtypes are represented on immune cells. In this review, we describe the distribution of serotonergic components in cells of the immune system and the impact of platelet-derived serotonin on these cells. In particular, we aim to understand the effect of serotonin on immune cell recruitment to sites of inflammation.