RESUMO
The process of cancer immunosurveillance is a mechanism of tumour suppression that can protect the host from cancer development throughout its lifetime1,2. However, it is unknown whether the effectiveness of cancer immunosurveillance fluctuates over a single day. Here we demonstrate that the initial time of day of tumour engraftment dictates the ensuing tumour size across mouse cancer models. Using immunodeficient mice as well as mice lacking lineage-specific circadian functions, we show that dendritic cells (DCs) and CD8+ T cells exert circadian anti-tumour functions that control melanoma volume. Specifically, we find that rhythmic trafficking of DCs to the tumour draining lymph node governs a circadian response of tumour-antigen-specific CD8+ T cells that is dependent on the circadian expression of the co-stimulatory molecule CD80. As a consequence, cancer immunotherapy is more effective when synchronized with DC functions, shows circadian outcomes in mice and suggests similar effects in humans. These data demonstrate that the circadian rhythms of anti-tumour immune components are not only critical for controlling tumour size but can also be of therapeutic relevance.
Assuntos
Linfócitos T CD8-Positivos , Ritmo Circadiano , Células Dendríticas , Melanoma , Animais , Humanos , Camundongos , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Imunoterapia/métodos , Melanoma/imunologia , Melanoma/patologia , Melanoma/terapia , Camundongos Endogâmicos C57BL , Antígeno B7-1 , Antígenos de Neoplasias/imunologia , Linfonodos , Ritmo Circadiano/imunologiaRESUMO
The nervous system detects environmental and internal stimuli and relays this information to immune cells via neurotransmitters and neuropeptides. This is essential to respond appropriately to immunogenic threats and to support system homeostasis. Lymph nodes (LNs) act as sentinels where adaptive immune responses are generated. They are richly innervated by peripheral sympathetic and sensory nerves, which are responsible for the local secretion of neurotransmitters by sympathetic fibers, such as norepinephrine, and neuropeptides by sensory fibers, including calcitonin gene-related peptide (CGRP) and substance P. Additionally, time-of-day-dependent oscillations in nerve activity are associated with differential immune responses, suggesting a potential role for neuroimmune interactions in coordinating immunity in a circadian fashion. Here, we discuss how LN activity is controlled by local innervation.
Assuntos
Linfonodos , Neurotransmissores , Peptídeo Relacionado com Gene de Calcitonina , Humanos , Linfonodos/inervação , Neuropeptídeos , Substância PRESUMO
Peripheral nerve injury can cause debilitating disease and immune cell-mediated destruction of the affected nerve. While the focus has been on the nerve-regenerative response, the effect of loss of innervation on lymph node function is unclear. Here, we show that the popliteal lymph node (popLN) receives direct neural input from the sciatic nerve and that sciatic denervation causes lymph node expansion. Loss of sympathetic, adrenergic tone induces the expression of IFN-γ in LN CD8 T cells, which is responsible for LN expansion. Surgery-induced IFN-γ expression and expansion can be rescued by ß2 adrenergic receptor agonists but not sensory nerve agonists. These data demonstrate the mechanisms governing the pro-inflammatory effect of loss of direct adrenergic input on lymph node function.
Assuntos
Adrenérgicos/metabolismo , Interferon gama/metabolismo , Linfonodos/patologia , Traumatismos dos Nervos Periféricos/patologia , Animais , Antígenos/imunologia , Autoimunidade , Axotomia , Linfócitos T CD8-Positivos/imunologia , Denervação , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Nervo Isquiático/imunologia , Nervo Isquiático/patologia , Transdução de SinaisRESUMO
Bacterial endotoxin-induced sepsis causes 30-40% of the deaths in the intensive care unit (ICU) globally, for which there is no pharmacotherapy. Lipopolysaccharide (LPS), a bacterial endotoxin, stimulates the Toll-like receptor (TLR)-4 signalling pathways to upregulate the expression of various inflammatory mediators. Here, we show that the TIRAP and c-Jun protein signalling complex forms in macrophages in response to LPS stimulation, which increases the AP1 transcriptional activity, thereby amplifying the expression of inflammatory mediators. Using a computer-aided molecular docking platform, we identified gefitinib as a putative inhibitor of the TIRAP-c-Jun signalling complex. Further, we demonstrated the ability of gefitinib to inhibit the interaction of TIRAP-c-Jun with in vitro experiments and with a mouse model of sepsis. Importantly, pre-treatment with gefitinib increased the survival of the mice that received a lethal dose of LPS compared to that of the controls. These findings verify the ability of gefitinib to directly disrupt the interaction of TIRAP and c-Jun, thereby inhibiting a major inflammatory response that is often observed in patients experiencing sepsis.