The tetraspan MS4A family in homeostasis, immunity, and disease

The 18 protein members of the human MS4A family are differentially expressed in different leukocyte subsets. The functions of these molecules have been largely overlooked. In humans and mice, MS4A proteins cluster in homo- and heterocomplexes, generating MS4A-enriched microdomains preferentially located in lipid rafts. MS4A proteins can regulate cell activation by working as ion channels or by modulating the signaling of other immunoreceptors, including the B cell receptor, other immunoglobulin receptors, PRRs (i.e., Dectin-1), or triggering receptors (i.e., TREM2). MS4A proteins may act as components of ‘sensing machineries’ and their expression in different combinations might contribute to fine-tuning immune cell activation. Immature and mature myelomonocytic cells, dendritic cells, and lymphoid cells express different repertoires of MS4A proteins under physiological or pathological conditions. They may have an important role in cancer, autoimmunity, and infection. MS4A genetic polymorphisms have been associated with human diseases, such as neurodegeneration. Based on the success of anti-CD20/MS4A1 monoclonal antibodies in malignancy and autoimmunity, these proteins might represent putative targets for innovative therapeutic strategies. The membrane-spanning 4A (MS4A) family includes 18 members with a tetraspan structure in humans. They are differentially and selectively expressed in immunocompetent cells, such as B cells (CD20/MS4A1) and macrophages (MS4A4A), and associate with, and modulate the signaling activity of, different classes of immunoreceptor, including pattern recognition receptors (PRRs) and Ig receptors. Evidence from preclinical models and genetic evidence from humans suggest that members of the MS4A family have key roles in different pathological settings, including cancer, infectious diseases, and neurodegeneration. Therefore, MS4A family members might serve as candidate biomarkers and therapeutic targets for various conditions. The membrane-spanning 4A (MS4A) family includes 18 members with a tetraspan structure in humans. They are differentially and selectively expressed in immunocompetent cells, such as B cells (CD20/MS4A1) and macrophages (MS4A4A), and associate with, and modulate the signaling activity of, different classes of immunoreceptor, including pattern recognition receptors (PRRs) and Ig receptors. Evidence from preclinical models and genetic evidence from humans suggest that members of the MS4A family have key roles in different pathological settings, including cancer, infectious diseases, and neurodegeneration. Therefore, MS4A family members might serve as candidate biomarkers and therapeutic targets for various conditions. anti-inflammatory macrophages activated by anti-inflammatory mediators (IL-4, IL-10, and glucocorticoids). extracellular deposits of amyloid β proteins that, together with tangle deposition, can generate the neuropathological manifestations of AD. immune reactions mediated by the complement system or NK cells, respectively; in the latter, the Fc portion of IgG antibodies triggers CD16 (FcγRIII)-dependent activation of NK cells, leading to lysis of targeted cells. major subset of myeloid DCs in blood. process mediated by ion exchange; generates charge imbalances across phagosomal membranes and allows vesicular acidification. imaging technique used to test whether two proteins are interacting with each other. RORγt+ subset of tissue-resident innate lymphoid cells; characterized by the expression of IL-17 and IL-22. immunotherapy aimed at improving the responsiveness of cytotoxic lymphocytes, based on the inhibition of immune checkpoint immunosuppressive molecules (e.g., PD-1). method used to reveal genetic risk variants. The main advantage of this technique is that it maximizes the power to detect subtle genetic effects of common traits. key component of the innate immune system; mediates caspase-1 activation and the secretion of Il1β/IL18 in response to microbial infections or cellular damage. located in the nasal epithelium; responsible for the detection and transmission of odorant information to the CNS. proteins expressed by innate immune cells, mainly belonging to the myeloid lineage, able to recognize conserved structures of pathogens. rare subset of circulating DCs; produce high amounts of type I interferons (IFN-I). member of the nuclear receptor family of DNA-binding transcription factors; mainly expressed by immune cells. infection and inflammation of the Fallopian tubes (also called salpinges). method suitable for the identification of protein–protein interactions. RORγt+ subset of T cells mainly residing at barrier tissues; characterized by the expression of IL-17. deposit of neurofibrillary tangles formed by hyperphosphorylation of the microtubule-associated protein known as tau. cluster of tetraspan proteins comprising mono- or heterocomplexes located in lipid rafts. proteins the structure of which crosses four times through the plasma membrane; can move laterally and interact with other membrane-associated molecules.