Cellular immune responses are orchestrated by an intricate balance of activating and inhibitory signals transmitted by cell surface receptors. Perturbations in this balance by overamplified or dysregulated signalling underlie many severe immunopathologies such as sepsis and cancer. In this work I describe the identification and characterisation of a novel, evolutionarily conserved immunoreceptor encoded within the human leukocyte receptor complex and syntenic region of mouse chromosome 7, named T cell-interacting, activating receptor on myeloid cells-1 (TARM1). The transmembrane region of TARM1 contained a conserved arginine residue, consistent with association with a signalling adaptor. Co-immunoprecipitation experiments confirmed that TARM1 associated with the ITAM adaptor FcR-gamma but not with DAP10 or DAP12. Flow cytometric screening of cells and tissues from pathogen-free mice showed that the TARM1 protein was constitutively expressed on the cell surface of mature and immature CD11b+Gr+ neutrophils isolated from bone marrow but not at peripheral sites. Following ip LPS treatment or systemic bacterial challenge, TARM1 protein expression was upregulated by myelocytes, mature neutrophils and inflammatory monocytes and TARM1+ cells were rapidly recruited to sites of inflammation. TARM1 expression was also upregulated by bone marrow-derived macrophages and dendritic cells following stimulation with TLR agonists in vitro. Ligation of the TARM1 receptor with specific antibody in the presence of TLR ligands, such as LPS, enhanced the secretion of proinflammatory cytokines by bone marrow-derived macrophages and primary mouse neutrophils, whereas TARM1 stimulation alone had no effect. Finally, an immobilised TARM1 Fc fusion protein suppressed CD4+ T cell activation and proliferation in vitro. These results suggest that a putative T cell ligand can interact with TARM1 receptor, resulting in bidirectional signalling and raising the T cell activation threshold while costimulating the release of proinflammatory cytokines by macrophages and neutrophils.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:763648 |
| Date | January 2018 |
| Creators | Radjabova, Valeria |
| Contributors | Trowsdale, John |
| Publisher | University of Cambridge |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.repository.cam.ac.uk/handle/1810/284078 |
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