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1.
Cell ; 187(11): 2690-2702.e17, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38723627

RESUMO

The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8+ T cells, are important parameters for the control of tumor growth and response to immunotherapy. Here, we show in murine and human cancers that these parameters exhibit circadian oscillations, driven by both the endogenous circadian clock of leukocytes and rhythmic leukocyte infiltration, which depends on the circadian clock of endothelial cells in the tumor microenvironment. To harness these rhythms therapeutically, we demonstrate that efficacy of chimeric antigen receptor T cell therapy and immune checkpoint blockade can be improved by adjusting the time of treatment during the day. Furthermore, time-of-day-dependent T cell signatures in murine tumor models predict overall survival in patients with melanoma and correlate with response to anti-PD-1 therapy. Our data demonstrate the functional significance of circadian dynamics in the tumor microenvironment and suggest the importance of leveraging these features for improving future clinical trial design and patient care.


Assuntos
Linfócitos T CD8-Positivos , Imunoterapia , Linfócitos do Interstício Tumoral , Camundongos Endogâmicos C57BL , Microambiente Tumoral , Animais , Humanos , Camundongos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Relógios Circadianos , Ritmo Circadiano , Células Endoteliais/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Melanoma/terapia , Melanoma/patologia , Microambiente Tumoral/imunologia
2.
Nat Immunol ; 22(11): 1375-1381, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34663979

RESUMO

Migration of leukocytes from the skin to lymph nodes (LNs) via afferent lymphatic vessels (LVs) is pivotal for adaptive immune responses1,2. Circadian rhythms have emerged as important regulators of leukocyte trafficking to LNs via the blood3,4. Here, we demonstrate that dendritic cells (DCs) have a circadian migration pattern into LVs, which peaks during the rest phase in mice. This migration pattern is determined by rhythmic gradients in the expression of the chemokine CCL21 and of adhesion molecules in both mice and humans. Chronopharmacological targeting of the involved factors abrogates circadian migration of DCs. We identify cell-intrinsic circadian oscillations in skin lymphatic endothelial cells (LECs) and DCs that cogovern these rhythms, as their genetic disruption in either cell type ablates circadian trafficking. These observations indicate that circadian clocks control the infiltration of DCs into skin lymphatics, a process that is essential for many adaptive immune responses and relevant for vaccination and immunotherapies.


Assuntos
Imunidade Adaptativa , Quimiotaxia , Relógios Circadianos , Células Dendríticas/imunologia , Linfonodos/imunologia , Vasos Linfáticos/imunologia , Pele/imunologia , Idoso , Animais , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Quimiocina CCL21/genética , Quimiocina CCL21/metabolismo , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Células Dendríticas/metabolismo , Feminino , Humanos , Linfonodos/metabolismo , Vasos Linfáticos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pele/metabolismo , Fatores de Tempo
3.
Nature ; 614(7946): 136-143, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36470303

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/imunologia
4.
Nat Commun ; 14(1): 476, 2023 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-36717561

RESUMO

The adaptive immune response is under circadian control, yet, why adaptive immune reactions continue to exhibit circadian changes over long periods of time is unknown. Using a combination of experimental and mathematical modeling approaches, we show here that dendritic cells migrate from the skin to the draining lymph node in a time-of-day-dependent manner, which provides an enhanced likelihood for functional interactions with T cells. Rhythmic expression of TNF in the draining lymph node enhances BMAL1-controlled ICAM-1 expression in high endothelial venules, resulting in lymphocyte infiltration and lymph node expansion. Lymph node cellularity continues to be different for weeks after the initial time-of-day-dependent challenge, which governs the immune response to vaccinations directed against Hepatitis A virus as well as SARS-CoV-2. In this work, we present a mechanistic understanding of the time-of-day dependent development and maintenance of an adaptive immune response, providing a strategy for using time-of-day to optimize vaccination regimes.


Assuntos
COVID-19 , Relógios Circadianos , Humanos , COVID-19/prevenção & controle , SARS-CoV-2 , Imunidade Adaptativa , Vacinação , Linfonodos
5.
Sci Immunol ; 7(72): eabm2465, 2022 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-35658012

RESUMO

The immune system is highly time-of-day dependent. Pioneering studies in the 1960s were the first to identify immune responses to be under a circadian control. Only in the last decade, however, have the molecular factors governing circadian immune rhythms been identified. These studies have revealed a highly complex picture of the interconnectivity of rhythmicity within immune cells with that of their environment. Here, we provide a global overview of the circadian immune system, focusing on recent advances in the rapidly expanding field of circadian immunology.


Assuntos
Ritmo Circadiano , Sistema Imunitário
6.
J Exp Med ; 218(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34086056

RESUMO

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 Sinais
7.
Nat Commun ; 11(1): 289, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029711

RESUMO

Voluntary action is a fundamental element of self-consciousness. The readiness potential (RP), a slow drift of neural activity preceding self-initiated movement, has been suggested to reflect neural processes underlying the preparation of voluntary action; yet more than fifty years after its introduction, interpretation of the RP remains controversial. Based on previous research showing that internal bodily signals affect sensory processing and ongoing neural activity, we here investigated the potential role of interoceptive signals in voluntary action and the RP. We report that (1) participants initiate voluntary actions more frequently during expiration, (2) this respiration-action coupling is absent during externally triggered actions, and (3) the RP amplitude is modulated depending on the respiratory phase. Our findings demonstrate that voluntary action is coupled with the respiratory system and further suggest that the RP is associated with fluctuations of ongoing neural activity that are driven by the involuntary and cyclic motor act of breathing.


Assuntos
Encéfalo/fisiologia , Variação Contingente Negativa , Respiração , Adulto , Química Encefálica , Eletroencefalografia , Feminino , Humanos , Masculino , Adulto Jovem
8.
Cell Res ; 31(11): 1146-1147, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34471238
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