Modulation of CD8+ T Cell Function by Beta2-Adrenergic Receptor Signaling




Estrada, Leonardo Daniel

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There is intimate crosstalk between the nervous system and the immune system. The nervous system can respond to immune system cues through afferent nerve endings. One effect of this response is the secretion of neurotransmitters in peripheral organs through efferent nerve endings. Primary and secondary immune organs are innervated predominantly by sympathetic nerve endings. The nerve termini are adrenergic and secrete norepinephrine upon stimulation, which can modulate immune cell function primarily through the beta2-adrenergic receptor (ADRB2). Our previous work has demonstrated that various subsets of CD8+ T cells have differential expression of the ADRB2 transcript. The role of ADRB2 signaling on the differentiation and acute effector functions of CD8+ T cells remains poorly understood. More importantly, its effect on CD8+ T cell memory development remains elusive. Therefore, I comprehensively addressed the role of ADRB2 signaling on different aspects of CD8+ T cell function. In the current body of work I demonstrate that intrinsic ADRB2 signaling downregulates CD8+ T cell acute effector functions, without affecting differentiation into effector cells. This is true with various forms of T cell receptor activation and with endogenous as well as pharmacological ADRB2 ligands. Furthermore, CD8+ T cell interferon-gamma secretion induced by innate cytokines was not affected. Finally, ADRB2-deficient CD8+ T cells fail to develop into memory cells after an in vivo viral infection. This effect is intrinsic to the ability of CD8+ T cells to signal through the ADRB2 as shown by bone marrow chimera experiments. The inability of ADRB2-deficient CD8+ T cells to develop into memory cells is accompanied by higher expression of several activation-related genes, as well as decreased expression of CD25 five days post-infection. However, restoration of CD25 expression in ADRB2-deficient cells with IL-2/anti-IL-2 treatment was unable to rescue memory development. Taken together, my results demonstrate for the first time that the sympathetic nervous system controls CD8+ T cell memory development through ADRB2 signaling on CD8+ T cells.

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