{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLAMF6, also known as NTB‐A, functions as a homotypic receptor that plays a critical role in innate immunity, particularly by modulating natural killer (NK) cell activity. Through self‐ligand interactions, SLAMF6 enhances NK cell cytotoxicity and degranulation, a process that can be perturbed in viral infections. For example, HIV proteins (Vpu) target SLAMF6 by altering its anterograde transport and glycosylation, thereby reducing its surface expression and impairing NK cell–mediated lysis of infected cells. In addition, engagement of SLAMF6 on NK cells also contributes to the “education” of NK cells, promoting responsiveness not only toward hematopoietic targets but also nonhematopoietic cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in innate cells, SLAMF6 acts as an important co‐stimulatory receptor on T lymphocytes. Engagement of SLAMF6—either via homophilic binding or in cooperation with signals delivered through the T-cell receptor (TCR) and conventional co-stimulators like CD28—augments T cell activation, proliferation, and cytokine production. Its intracellular signaling involves recruitment of adaptor proteins such as SAP and EAT-2, leading to differential regulation of cytotoxic function versus cytokine secretion. Moreover, SLAMF6 participation is pivotal for proper restimulation-induced cell death (RICD) and for the induction of Th1 and even Th17 responses via modulation of downstream NF-κB-associated genes and transcription factors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructurally, the ectodomain of SLAMF6 forms a rod-like configuration that underlies its specific homophilic binding and subsequent signal transduction, as detailed by crystallographic studies. This structural feature, together with its reviewed signaling functions, underpins the receptor’s involvement in various disease settings. For instance, altered SLAMF6 expression or function has been implicated in autoimmune disorders such as systemic lupus erythematosus and severe aplastic anemia, where defective costimulatory signaling can skew cytokine profiles and T cell homeostasis. In the context of cancer, soluble forms of SLAMF6 have shown promise in enhancing T cell effector functions within the tumor microenvironment, correlating with improved prognoses in melanoma and breast cancer patients."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ruediger M Flaig, Sebastian Stark, Carsten Watzl "}, {"type": "b", "children": [{"type": "t", "text": "Cutting edge: NTB-A activates NK cells via homophilic interaction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.172.11.6524"}], "href": "https://doi.org/10.4049/jimmunol.172.11.6524"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15153464"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15153464"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Ankur H Shah, Bharatwaj Sowrirajan, Zachary B Davis, et al. 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