Abstract
CD8+ T cells are major components of adaptive immunity and confer robust protective cellular immunity, which requires adequate T-cell numbers, targeted migration, and efficient T-cell proliferation. Altered CD8+ T-cell homeostasis and impaired proliferation result in dysfunctional immune response to infection or tumorigenesis. However, intrinsic factors controlling CD8+ T-cell homeostasis and immunity remain largely elusive. Here, we demonstrate the prominent role of Brd4 on CD8+ T cell homeostasis and immune response. By upregulating Myc and GLUT1 expression, Brd4 facilitates glucose uptake and energy production in mitochondria, subsequently supporting naïve CD8+ T-cell survival. Besides, Brd4 promotes the trafficking of naïve CD8+ T cells partially through maintaining the expression of homing receptors (CD62L and LFA-1). Furthermore, Brd4 is required for CD8+ T cell response to antigen stimulation, as Brd4 deficiency leads to a severe defect in clonal expansion and terminal differentiation by decreasing glycolysis. Importantly, as JQ1, a pan-BRD inhibitor, severely dampens CD8+ T-cell immune response, its usage as an anti-tumor agent or latency-reversing agent for human immunodeficiency virus type I (HIV-1) should be more cautious. Collectively, our study identifies a previously-unexpected role of Brd4 in the metabolic regulation of CD8+ T cell-mediated immune surveillance and also provides a potential immunomodulation target.
Highlights
T-cell homeostasis maintenance is important for protective immunity and facilitates effective recognition of diverse antigens
Because targeting Brd4 slows down tumor growth partially through downregulating Myc expression, we investigated whether the downregulation of glucose transporter GLUT1 resulted from the reduced Myc expression in Brd4-/- CD8+ T cells [30, 41]
As naïve CD8+ T cells largely depend on glucose uptake to undergo oxidative phosphorylation, which supports naïve T-cell survival, we explored whether Brd4 deficiency could cause impaired cell survival by decreasing glucose metabolism [10, 13]
Summary
T-cell homeostasis maintenance is important for protective immunity and facilitates effective recognition of diverse antigens. Altered T-cell homeostasis frequently results in a dysfunctional immune response to infections and tumors, as well as the development of autoimmunity [1]. The normal maintenance of CD8+ T-cell homeostasis is critical for the host to execute immune surveillance and prevent autoimmune diseases. Naïve T cells continually recirculate between peripheral circulation and secondary lymphoid organs to receive stimulation by homeostatic cues, which enhance T-cell survival and homeostasis proliferation [3]. Homing receptors, including CD62L, CCR7, and LFA-1, are responsible for naïve T cells transmigrating from circulation into lymph nodes [5]. Transcription factors Foxo and Klf maintain peripheral naïve T-cell homeostasis by regulating migration receptor expression, including CD62L, CCR7 and S1PR1, to license naïve T cells for normal trafficking and survival [6,7,8]. Energy production in mitochondria is required for constant naïve T-cell migration [9]
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