Background: T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain\n(TIGIT) and programmed cell death protein 1 (PD-1) are important inhibitory receptors that associate with\nT cell exhaustion in acute myeloid leukemia (AML). In this study, we aimed to determine the underlying\ntranscriptional mechanisms regulating these inhibitory pathways. Specifically, we investigated the role of\ntranscription factor B lymphocyte-induced maturation protein 1 (Blimp-1) in T cell response and transcriptional\nregulation of TIGIT and PD-1 in AML.\nMethods: Peripheral blood samples collected from patients with AML were used in this study. Blimp-1 expression\nwas examined by flow cytometry. The correlation of Blimp-1 expression to clinical characteristics of AML patients was\nanalyzed. Phenotypic and functional studies of Blimp-1-expressing T cells were performed using flow cytometry-based\nassays. Luciferase reporter assays and ChIP assays were applied to assess direct binding and transcription activity of\nBlimp-1. Using siRNA to silence Blimp-1, we further elucidated the regulatory role of Blimp-1 in the TIGIT and PD-1\nexpression and T cell immune response.\nResults: Blimp-1 expression is elevated in T cells from AML patients. Consistent with exhaustion, Blimp-1+ T cells\nupregulate multiple inhibitory receptors including PD-1 and TIGIT. In addition, they are functionally impaired\nmanifested by low cytokine production and decreased cytotoxicity capacity. Importantly, the functional defect is\nreversed by inhibition of Blimp-1 via siRNA knockdown. Furthermore, Blimp-1 binds to the promoters of PD-1 and\nTIGIT and positively regulates their expression.\nConclusions: Our study demonstrates an important inhibitory effect of Blimp-1 on T cell response in AML; thus,\ntargeting Blimp-1 and its regulated molecules to improve the immune response may provide effective leukemia\ntherapeutics.
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