RESUMEN
Glucocorticoids are steroid hormones with strong anti-inflammatory and immunosuppressive effects that are produced in a diurnal fashion. Although glucocorticoids have the potential to induce interleukin-7 receptor (IL-7R) expression in T cells, whether they control T cell homeostasis and responses at physiological concentrations remains unclear. We found that glucocorticoid receptor signaling induces IL-7R expression in mouse T cells by binding to an enhancer of the IL-7Rα locus, with a peak at midnight and a trough at midday. This diurnal induction of IL-7R supported the survival of T cells and their redistribution between lymph nodes, spleen, and blood by controlling expression of the chemokine receptor CXCR4. In mice, T cell accumulation in the spleen at night enhanced immune responses against soluble antigens and systemic bacterial infection. Our results reveal the immunoenhancing role of glucocorticoids in adaptive immunity and provide insight into how immune function is regulated by the diurnal rhythm.
Asunto(s)
Ritmo Circadiano/fisiología , Glucocorticoides/farmacología , Receptores CXCR4/fisiología , Receptores de Interleucina-7/fisiología , Linfocitos T/inmunología , Animales , Células Cultivadas , Quimiocina CXCL12/biosíntesis , Femenino , Memoria Inmunológica , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores de Glucocorticoides/fisiologíaRESUMEN
IL-7 and IL-2 are evolutionarily related cytokines that play critical roles in the development and expansion of immune cells. Although both IL-7R and IL-2R activate similar signaling molecules, whether their signals have specific or overlapping functions during lymphocyte differentiation remains unclear. To address this question, we generated IL-7R α-chain (IL-7Rα)/IL-2R ß-chain (IL-24ß) (72R) knock-in mice expressing a chimeric receptor consisting of the extracellular domain of IL-7Rα and the intracellular domain of IL-2Rß under the control of the endogenous IL-7Rα promoter. Notably, this 72R receptor induced higher levels of STAT5 and Akt phosphorylation in T cells. In the periphery of 72R mice, the number of T cells, B cells, and type 2 innate lymphoid cells (ILC2s) was increased, whereas early T cell progenitors and double-negative 2 thymocytes were reduced in the thymus. In addition, cell proliferation and Notch signaling were impaired in the early thymocytes of 72R mice, leading to their differentiation into thymic B cells. Interestingly, ILC2s were increased in the thymus of 72R mice. Early T cell progenitors from 72R mice, but not from wild-type mice, differentiated into NK cells and ILC2-like cells when cocultured with a thymic stromal cell line. Thus, this study indicates that the chimeric 72R receptor transduces more robust signals than the authentic IL-7Rα, thereby inducing the alternative differentiation of T cell progenitors into other cell lineages. This suggests that cytokine receptors may provide instructive signals for cell fate decisions.
RESUMEN
The IL-7R regulates the homeostasis, activation, and distribution of T cells in peripheral tissues. Although several transcriptional enhancers that regulate IL-7Rα expression in αß T cells have been identified, enhancers active in γδ T cells remain unknown. In this article, we discovered an evolutionarily conserved noncoding sequence (CNS) in intron 2 of the IL-7Rα-chain (IL-7Rα) locus and named this region CNS9. CNS9 contained a conserved retinoic acid receptor-related orphan receptor (ROR)-responsive element (RORE) and exerted RORγt-dependent enhancer activity in vitro. Mice harboring point mutations in the RORE in CNS9 (CNS9-RORmut) showed reduced IL-7Rα expression in IL-17-producing Vγ4+ γδ T cells. In addition, the cell number and IL-17A production of Vγ4+ γδ T cells were reduced in the adipose tissue of CNS9-RORmut mice. Consistent with the reduction in IL-17A, CNS9-RORmut mice exhibited decreased IL-33 expression in the adipose tissue, resulting in fewer regulatory T cells and glucose intolerance. The CNS9-ROR motif was partially responsible for IL-7Rα expression in RORγt+ regulatory T cells, whereas IL-7Rα expression was unaffected in RORγt-expressing Vγ2+ γδ T cells, Th17 cells, type 3 innate lymphoid cells, and invariant NKT cells. Our results indicate that CNS9 is a RORΕ-dependent, Vγ4+ γδ T cell-specific IL-7Rα enhancer that plays a critical role in adipose tissue homeostasis via regulatory T cells, suggesting that the evolutionarily conserved RORΕ in IL-7Rα intron 2 may influence the incidence of type 2 diabetes.
Asunto(s)
Elementos de Facilitación Genéticos , Intrones , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Receptores de Antígenos de Linfocitos T gamma-delta , Animales , Ratones , Intrones/genética , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Elementos de Facilitación Genéticos/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Glucosa/metabolismo , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/metabolismo , Ratones Endogámicos C57BL , Células Th17/inmunología , Interleucina-17/metabolismo , Interleucina-17/genética , Humanos , Tejido Adiposo/metabolismo , Tejido Adiposo/inmunologíaRESUMEN
Group 2 innate lymphoid cells (ILC2s) are critical for the immune response against parasite infection and tissue homeostasis and involved in the pathogenesis of allergy and inflammatory diseases. Although multiple molecules positively regulating ILC2 development and activation have been extensively investigated, the factors limiting their population size and response remain poorly studied. Here, we found that CD45, a membrane-bound tyrosine phosphatase essential for T cell development, negatively regulated ILC2s in a cell-intrinsic manner. ILC2s in CD45-deficient mice exhibited enhanced proliferation and maturation in the bone marrow and hyperactivated phenotypes in the lung with high glycolytic capacity. Furthermore, CD45 signaling suppressed the type 2 inflammatory response by lung ILC2s and alleviated airway inflammation and pulmonary fibrosis. Finally, the interaction with galectin-9 influenced CD45 signaling in ILC2s. These results demonstrate that CD45 is a cell-intrinsic negative regulator of ILC2s and prevents lung inflammation and fibrosis via ILC2s.
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Fibrosis Pulmonar , Animales , Ratones , Fibrosis Pulmonar/prevención & control , Inmunidad Innata , Linfocitos , Inflamación , Transducción de SeñalRESUMEN
Steroid hormones induce the transcription of target genes by activating nuclear receptors. Early transcriptional response to various stimuli, including hormones, involves the active catalysis of topoisomerase II (TOP2) at transcription regulatory sequences. TOP2 untangles DNAs by transiently generating double-strand breaks (DSBs), where TOP2 covalently binds to DSB ends. When TOP2 fails to rejoin, called "abortive" catalysis, the resulting DSBs are repaired by tyrosyl-DNA phosphodiesterase 2 (TDP2) and non-homologous end-joining (NHEJ). A steroid, cortisol, is the most important glucocorticoid, and dexamethasone (Dex), a synthetic glucocorticoid, is widely used for suppressing inflammation in clinics. We here revealed that clinically relevant concentrations of Dex and physiological concentrations of cortisol efficiently induce DSBs in G1 phase cells deficient in TDP2 and NHEJ. The DSB induction depends on glucocorticoid receptor (GR) and TOP2. Considering the specific role of TDP2 in removing TOP2 adducts from DSB ends, induced DSBs most likely represent stalled TOP2-DSB complexes. Inhibition of RNA polymerase II suppressed the DSBs formation only modestly in the G1 phase. We propose that cortisol and Dex frequently generate DSBs through the abortive catalysis of TOP2 at transcriptional regulatory sequences, including promoters or enhancers, where active TOP2 catalysis occurs during early transcriptional response.
Asunto(s)
Roturas del ADN de Doble Cadena , Factores de Transcripción , Factores de Transcripción/metabolismo , Proteínas de Unión al ADN/metabolismo , Glucocorticoides/farmacología , Reparación del ADN , Proteínas Nucleares/metabolismo , Hidrocortisona/farmacología , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismo , ADN-Topoisomerasas de Tipo II/genética , ADN-Topoisomerasas de Tipo II/metabolismo , ADN/genéticaRESUMEN
Interleukin-7 (IL-7) is a cytokine critical for the development and maintenance of group 2 innate lymphoid cells (ILC2s). ILC2s are resident in peripheral tissues such as the intestine and lung. However, whether IL-7 produced in the lung plays a role in the maintenance and function of lung ILC2s during airway inflammation remains unknown. IL-7 was expressed in bronchoalveolar epithelial cells and lymphatic endothelial cells (LECs). To investigate the role of local IL-7 in lung ILC2s, we generated two types of IL-7 conditional knockout (IL-7cKO) mice: Sftpc-Cre (SPC-Cre) IL-7cKO mice specific for bronchial epithelial cells and type 2 alveolar epithelial cells and Lyve1-Cre IL-7cKO mice specific for LECs. In steady state, ILC2s were located near airway epithelia, although lung ILC2s were unchanged in the two lines of IL-7cKO mice. In papain-induced airway inflammation dependent on innate immunity, lung ILC2s localized near bronchia via CCR4 expression, and eosinophil infiltration and type 2 cytokine production were reduced in SPC-Cre IL-7cKO mice. In contrast, in house dust mite (HDM)-induced airway inflammation dependent on adaptive immunity, lung ILC2s localized near lymphatic vessels via their CCR2 expression 2 weeks after the last challenge. Furthermore, lung ILC2s were decreased in Lyve1-Cre IL-7cKO mice in the HDM-induced inflammation because of decreased cell survival and proliferation. Finally, administration of anti-IL-7 antibody attenuated papain-induced inflammation by suppressing the activation of ILC2s. Thus, this study demonstrates that IL-7 produced by bronchoalveolar epithelial cells and LECs differentially controls the activation and maintenance of lung ILC2s, where they are localized in airway inflammation.
Asunto(s)
Inmunidad Innata , Interleucina-7 , Ratones , Animales , Células Endoteliales/metabolismo , Papaína , Linfocitos , Pulmón , Inmunidad Adaptativa , Inflamación , Citocinas/metabolismo , Interleucina-33RESUMEN
Asthma is more common in females than males after adolescence. However, the mechanism of the sex bias in the prevalence of asthma remains unknown. To test whether sex steroid hormones have some roles in T cells during development of asthma, we analyzed airway inflammation in T cell-specific androgen receptor (AR)- and estrogen receptor (ER)-deficient mice. T cell-specific AR-deficient male mice developed severer house dust mite-induced allergic airway inflammation than did control male mice, whereas T cell-specific ERα- and ERß-deficient female mice exhibited a similar degree of inflammation as for control female mice. Furthermore, administration of dihydrotestosterone reduced cytokine production of Th2 cells from control, but not AR-deficient, naive T cells. Transfer of OT-II transgenic AR-deficient Th2 cells into wild-type mice induced severer allergic airway inflammation by OVA than transfer of control Th2 cells. Gene expression profiling suggested that the expression of genes related with cell cycle and Th2 differentiation was elevated in AR-deficient Th2 cells, whereas expression of dual specificity phosphatase (DUSP)-2, a negative regulator of p38, was downregulated. In addition, a chromatin immunoprecipitation assay suggested that AR bound to an AR motif in the 5' untranslated region of the Dusp2 gene in Th2 cells. Furthermore, the Dusp2 promoter with a wild-type AR motif, but not a mutated motif, was transactivated by dihydrotestosterone in a reporter assay. Finally, forced expression of DUSP-2 by retrovirus vector reduced IL-4 expression in Th2 cells. Thus, these results suggest that androgen signaling suppresses cytokine production of Th2 cells by inducing DUSP-2, explaining, in part, the sex bias of asthma after adolescence.
Asunto(s)
Asma , Hipersensibilidad , Regiones no Traducidas 5' , Andrógenos/metabolismo , Animales , Asma/genética , Asma/metabolismo , Dihidrotestosterona , Modelos Animales de Enfermedad , Fosfatasas de Especificidad Dual/metabolismo , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/genética , Femenino , Hipersensibilidad/metabolismo , Inflamación/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Ratones , Ratones Noqueados , Receptores Androgénicos/genética , Receptores de Estrógenos/genética , Células Th17/metabolismo , Células Th2/metabolismoRESUMEN
T cell development and homeostasis requires IL-7R α-chain (IL-7Rα) signaling. Tyrosine Y449 of the IL-7Rα is essential to activate STAT5 and PI3K, whereas PI3K recruitment requires IL-7Rα methionine M452. How IL-7Rα activates and regulates both signaling pathways differentially remains unclear. To characterize differential signaling, we established two lines of IL-7Rα mutant mice: IL-7R-Y449F mice and IL-7R-M452L mice. IL-7R-Y449F mice showed decreased PI3K and STAT5 signals, whereas IL-7R-M452L mice showed decreased PI3K but significantly increased STAT5 signaling, owing to a competition between PI3K and STAT5 signaling through Y449 of IL-7Rα. The number of T, B, and mature innate lymphoid cells were markedly reduced in IL-7R-Y449F mice, whereas IL-7R-M452L mice showed impaired early T cell development and memory precursor effector T cell maintenance with the downregulation of transcription factor T cell factor-1. Peripheral T cell numbers increased in IL-7R-M452L mice with enhanced survival and homeostatic proliferation. Furthermore, although wild type and IL-7R-Y449F mice showed comparable Th1/Th2 differentiation, IL-7R-M452L mice exhibited impaired Th17 differentiation. We conclude that PI3K competes with STAT5 under IL-7Rα and maintains an appropriate signal balance for modulating T cell development and homeostasis. To our knowledge, this study provides a new insight into complex regulation of IL-7Rα signaling, which supports immune development and responses.
Asunto(s)
Homeostasis/inmunología , Fosfatidilinositol 3-Quinasas/inmunología , Receptores de Interleucina-7/inmunología , Factor de Transcripción STAT5/inmunología , Linfocitos T/inmunología , Animales , Diferenciación Celular/inmunología , Inmunidad Innata , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Fosfatidilinositol 3-Quinasas/metabolismo , Receptores de Interleucina-7/metabolismo , Factor de Transcripción STAT5/metabolismo , Transducción de Señal/inmunologíaRESUMEN
Steroid hormones, especially glucocorticoids, androgens, and estrogens, have profound influence on immunity. Recent studies using cell-type specific steroid hormone receptor-deficient mice have revealed the precise roles of some of these hormones in the immune system. Glucocorticoids are known to have strong anti-inflammatory and immunosuppressive effects and pleiotropic effects on innate and adaptive immune responses. They suppress the production of inflammatory cytokines by macrophages and DCs and the production of IFN-γ by NK cells, thus inhibiting innate immunity. By contrast, glucocorticoids enhance the immune response by inducing the expression of IL-7R and CXCR4 in T cells and the accumulation of T cells in lymphoid organs in accordance with the diurnal change of the glucocorticoid concentration. Thus, glucocorticoids suppress innate immunity but enhance adaptive immunity. Androgens suppress the homeostasis and activation of ILC2s and the differentiation of Th2 and Th17 cells and enhance the suppressive function of Tregs, thereby alleviating allergic airway inflammation. Thus, these steroid hormones have pleiotropic functions in the immune system. Further investigations are awaited on the regulation of immunity and allergy by estrogens using cell-specific steroid hormone receptor-deficient mice.
Asunto(s)
Hipersensibilidad , Inmunidad Innata , Animales , Citocinas/metabolismo , Estrógenos , Glucocorticoides , Linfocitos , Ratones , EsteroidesRESUMEN
Environmental cues such as the day-night cycle or stressors trigger the production of glucocorticoids (GCs) by the adrenal cortex. GCs are well known for their anti-inflammatory effects that suppress the production of inflammatory cytokines and induce the apoptosis of lymphocytes. Recent studies in mice, however, have revealed pro-inflammatory effects. The diurnal oscillation of GCs induces the expression of IL-7 receptor α (IL-7Rα) and C-X-C motif chemokine receptor 4 (CXCR4) at the active phase, which drives the diurnal homing of T cells into lymphoid organs. This accumulation of T cells at the active phase enhances T-cell priming against bacterial infection and antigen immunization, leading to an increase of effector CD8 T cells and antibody production. GCs induced by moderate stress trigger the homing of memory CD8 T cells into the bone marrow and support the maintenance and response of these cells. Thus, endogenous GCs have a self-defense function to enhance adaptive immune responses. By contrast, strong stress induces even higher GC levels and causes chronic inflammation and autoimmunity. Because GCs can enhance the differentiation and function of T-helper 2 (Th2) and Th17 cells, high stress-induced GC levels might enhance inflammation via Th17 cell differentiation. Overall, the positive and negative effects of GCs may regulate the balance between normal immune responses and susceptibility to infections and inflammatory diseases.
Asunto(s)
Ritmo Circadiano/inmunología , Glucocorticoides/inmunología , Animales , Humanos , Estrés Oxidativo/inmunologíaRESUMEN
Interleukin-15 (IL-15) is a cytokine critical for maintenance of intestinal intra-epithelial lymphocytes (IELs), especially CD8ααâ+ IELs (CD8αα IELs). In the intestine, IL-15 is produced by intestinal epithelial cells (IECs), blood vascular endothelial cells (BECs) and hematopoietic cells. However, the precise role of intestinal IL-15 on IELs is still unknown. To address the question, we generated two kinds of IL-15 conditional knockout (IL-15cKO) mice: villin-Cre (Vil-Cre) and Tie2-Cre IL-15cKO mice. IEC-derived IL-15 was specifically deleted in Vil-Cre IL-15cKO mice, whereas IL-15 produced by BECs and hematopoietic cells was deleted in Tie2-Cre IL-15cKO mice. The cell number and frequency of CD8αα IELs and NK IELs were significantly reduced in Vil-Cre IL-15cKO mice. By contrast, CD8αα IELs were unchanged in Tie2-Cre IL-15cKO mice, indicating that IL-15 produced by BECs and hematopoietic cells is dispensable for CD8αα IELs. Expression of an anti-apoptotic factor, Bcl-2, was decreased, whereas Fas expression was increased in CD8αα IELs of Vil-Cre IL-15cKO mice. Forced expression of Bcl-2 by a Bcl-2 transgene partially restored CD8αα IELs in Vil-Cre IL-15cKO mice, suggesting that some IL-15 signal other than Bcl-2 is required for maintenance of CD8αα IELs. Furthermore, granzyme B production was reduced, whereas PD-1 expression was increased in CD8αα IELs of Vil-Cre IL-15cKO mice. These results collectively suggested that IEC-derived IL-15 is essential for homeostasis of IELs by promoting their survival and functional maturation.
Asunto(s)
Células Endoteliales/inmunología , Interleucina-15/inmunología , Intestinos/citología , Intestinos/inmunología , Linfocitos Intraepiteliales/citología , Linfocitos Intraepiteliales/inmunología , Animales , Femenino , Interleucina-15/deficiencia , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones TransgénicosRESUMEN
Interleukin (IL)-7 is a cytokine essential for T lymphocyte development and homeostasis. However, little is known about the roles of IL-7 receptor α-chain (IL-7Rα) in late stages of T-cell development. To address this question, we established IL-7Rα-floxed mice and crossed them with CD4-Cre transgenic mice. Resultant IL-7R conditional knockout (IL-7RcKO) mice exhibited marked reduction in CD8 single positive (SP) T cells, regulatory T cells (Tregs), and natural killer T (NKT) cells in thymus. The proportion and proliferation of both mature CD4SP and CD8SP thymocytes were decreased without affecting Runx expression. In addition, expression of the glucocorticoid-induced TNF receptor was reduced in CD4SP and CD8SP thymocytes, and expression of CD5 was decreased in CD8SP thymocytes. IL-7RcKO mice also showed impaired Treg and NKT cell proliferation and inhibition of NKT cell maturation. Bcl-2 expression was reduced in CD4SP and CD8SP thymocytes but not in Tregs and NKT cells, and introduction of a Bcl-2 transgene rescued frequency and CD5 expression of CD8SP thymocytes. Furthermore, IL-7RcKO mice exhibited greatly increased numbers of B cells and, to a lesser extent, γδ T and dendritic cells in thymus. Overall, this study demonstrates that IL-7Rα differentially controls development and maturation of thymocyte subpopulations in late developmental stages and suggests that IL-7R expression on αß T cells suppresses development of other cell lineages in thymus.
Asunto(s)
Diferenciación Celular/inmunología , Subunidad alfa del Receptor de Interleucina-7/metabolismo , Subgrupos Linfocitarios/fisiología , Timocitos/citología , Animales , Bromodesoxiuridina , Subunidades alfa del Factor de Unión al Sitio Principal/metabolismo , Citometría de Flujo , Subunidad alfa del Receptor de Interleucina-7/genética , Subgrupos Linfocitarios/metabolismo , Ratones , Ratones Noqueados , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Timocitos/metabolismoRESUMEN
Group 1 innate lymphoid cells (G1-ILCs), including circulating natural killer (NK) cells and tissue-resident type 1 ILCs (ILC1s), are innate immune sentinels critical for responses against infection and cancer. In contrast to relatively uniform NK cells through the body, diverse ILC1 subsets have been characterized across and within tissues in mice, but their developmental and functional heterogeneity remain unsolved. Here, using multimodal in vivo approaches including fate-mapping and targeting of the interleukin 15 (IL-15)-producing microenvironment, we demonstrate that liver parenchymal niches support the development of a cytotoxic ILC1 subset lacking IL-7 receptor (7 R- ILC1s). During ontogeny, fetal liver (FL) G1-ILCs arise perivascularly and then differentiate into 7 R- ILC1s within sinusoids. Hepatocyte-derived IL-15 supports parenchymal development of FL G1-ILCs to maintain adult pool of 7 R- ILC1s. IL-7R+ (7R+) ILC1s in the liver, candidate precursors for 7 R- ILC1s, are not essential for 7 R- ILC1 development in physiological conditions. Functionally, 7 R- ILC1s exhibit killing activity at steady state through granzyme B expression, which is underpinned by constitutive mTOR activity, unlike NK cells with exogenous stimulation-dependent cytotoxicity. Our study reveals the unique ontogeny and functions of liver-specific ILC1s, providing a detailed interpretation of ILC1 heterogeneity.
Asunto(s)
Interleucina-15 , Linfocitos , Ratones , Animales , Linfocitos/metabolismo , Interleucina-15/metabolismo , Inmunidad Innata , Receptores de Interleucina-7/metabolismo , Células Asesinas Naturales , HígadoRESUMEN
Natural killer (NK) cells are innate immune cells critical for protective immune responses against infection and cancer. Although NK cells differentiate in the bone marrow (BM) in an interleukin-15 (IL-15)-dependent manner, the cellular source of IL-15 remains elusive. Using NK cell reporter mice, we show that NK cells are localized in the BM in scattered and clustered manners. NK cell clusters overlap with monocyte and dendritic cell accumulations, whereas scattered NK cells require CXCR4 signaling. Using cell-specific IL-15-deficient mice, we show that hematopoietic cells, but not stromal cells, support NK cell development in the BM through IL-15. In particular, IL-15 produced by monocytes and dendritic cells appears to contribute to NK cell development. These results demonstrate that hematopoietic cells are the IL-15 niche for NK cell development in the BM and that BM NK cells are present in scattered and clustered compartments by different mechanisms, suggesting their distinct functions in the immune response.
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Médula Ósea , Interleucina-15 , Ratones , Animales , Células de la Médula Ósea , Diferenciación Celular , Células Asesinas NaturalesRESUMEN
Invariant natural killer T (iNKT) cells are a group of innate-like T lymphocytes that recognize lipid antigens. They are supposed to be tissue resident and important for systemic and local immune regulation. To investigate the heterogeneity of iNKT cells, we recharacterized iNKT cells in the thymus and peripheral tissues. iNKT cells in the thymus were divided into three subpopulations by the expression of the natural killer cell receptor CD244 and the chemokine receptor CXCR6 and designated as C0 (CD244-CXCR6-), C1 (CD244-CXCR6+), or C2 (CD244+CXCR6+) iNKT cells. The development and maturation of C2 iNKT cells from C0 iNKT cells strictly depended on IL-15 produced by thymic epithelial cells. C2 iNKT cells expressed high levels of IFN-γ and granzymes and exhibited more NK cell-like features, whereas C1 iNKT cells showed more T cell-like characteristics. C2 iNKT cells were influenced by the microbiome and aging and suppressed the expression of the autoimmune regulator AIRE in the thymus. In peripheral tissues, C2 iNKT cells were circulating that were distinct from conventional tissue-resident C1 iNKT cells. Functionally, C2 iNKT cells protected mice from the tumor metastasis of melanoma cells by enhancing antitumor immunity and promoted antiviral immune responses against influenza virus infection. Furthermore, we identified human CD244+CXCR6+ iNKT cells with high cytotoxic properties as a counterpart of mouse C2 iNKT cells. Thus, this study reveals a circulating subset of iNKT cells with NK cell-like properties distinct from conventional tissue-resident iNKT cells.
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Células T Asesinas Naturales , Ratones , Humanos , Animales , Células T Asesinas Naturales/metabolismo , Células T Asesinas Naturales/patología , Interleucina-15 , Antivirales , Granzimas , Receptores de Células Asesinas Naturales , Receptores de Quimiocina/metabolismo , LípidosRESUMEN
Glucocorticoids (GCs) are a class of steroid hormones secreted from the adrenal cortex. Their production is controlled by circadian rhythm and stress, the latter of which includes physical restraint, hunger, and inflammation. Importantly, GCs have various effects on immunity, metabolism, and cognition, including pleiotropic effects on the immune system. In general, GCs have strong anti-inflammatory and immunosuppressive effects. Indeed, they suppress inflammatory cytokine expression and cell-mediated immunity, leading to increased risks of some infections. However, recent studies have shown that endogenous GCs induced by the diurnal cycle and dietary restriction enhance immune responses against some infections by promoting the survival, redistribution, and response of T and B cells via cytokine and chemokine receptors. Furthermore, although GCs are reported to reduce expression of Th2 cytokines, GCs enhance type 2 immunity and IL-17-associated immunity in some stress conditions. Taken together, GCs have both immunoenhancing and immunosuppressive effects on the immune system.
Asunto(s)
Ritmo Circadiano/inmunología , Glucocorticoides/inmunología , Sistema Inmunológico/inmunología , Animales , Humanos , Estrés Fisiológico/inmunologíaRESUMEN
Animals receive environmental stimuli from neural signals in order to produce hormones that control immune responses. Glucocorticoids (GCs) are a group of steroid hormones produced in the adrenal cortex and well-known mediators for the nervous and immune systems. GC secretion is induced by circadian rhythm and stress, and plasma GC levels are high at the active phase of animals and under stress condition. Clinically, GCs are used for allergies, autoimmunity, and chronic inflammation, because they have strong anti-inflammatory effects and induce the apoptosis of lymphocytes. Glucocorticoid receptor (GR) acts as a transcription factor and represses the expression of inflammatory cytokines, chemokines, and prostaglandins by binding to its motif, glucocorticoid-response element, or to other transcription factors. In mice, GR suppresses the antigen-stimulated inflammation mediated by macrophages, dendritic cells, and epithelial cells, and impairs cytotoxic immune responses by downregulating interferon-γ production and inhibiting the development of type-1 helper T cells, CD8+ T cells, and natural killer cells. These immune inhibitory effects prevent lethality by excessive inflammation, but at the same time increase the susceptibility to infection and cancer. GCs can also activate the immune system. The circadian cycle of GC secretion controls the diurnal oscillations of the distribution and response of T cells, thus supporting T cell maintenance and effective immune protection against infection. Moreover, several reports have shown that GR has the potential to enhance the activities of Th2, Th17, and immunoglobulin-producing B cells. Stress has two different effects on immune responses: immune suppression to cause mortality by infection and cancer, and excessive immune activation to induce chronic inflammation and autoimmune disease. Consistently, stress-induced GCs strongly suppress cell-mediated immunity and cause viral infection and tumor development. They may also enhance the development of pathogenic helper T cells and cause tissue damage through neural and intestinal inflammation. Past studies have reported the positive and negative effects of GCs on the immune system. These opposing properties of GCs may regulate the immune balance between the responsiveness to antigens and excessive inflammation in steady-state and stress conditions.
Asunto(s)
Glucocorticoides/inmunología , Inmunidad , Animales , Citocinas , Humanos , Hipersensibilidad , Ratones , Receptores de Glucocorticoides , Linfocitos T Colaboradores-InductoresRESUMEN
Animals have evolved circadian rhythms to adapt to the 24-h day-night cycle. Circadian rhythms are controlled by molecular clocks in the brain and periphery, which is driven by clock genes. The circadian rhythm is propagated from the brain to the periphery by nerves and hormones. Glucocorticoids (GCs) are a class of steroid hormones produced by the adrenal cortex under the control of the circadian rhythm and the stress. GCs have both positive and negative effects on the immune system. Indeed, they are well known for their strong anti-inflammatory and immunosuppressive effects. Endogenous GCs inhibit the expression of inflammatory cytokines and chemokines at the active phase of mice, regulating the circadian rhythm of tissue inflammation. In addition, GCs induce the rhythmic expression of IL-7R and CXCR4 on T cells, which supports T cell maintenance and homing to lymphoid tissues. Clock genes and adrenergic neural activity control the T cell migration and immune response. Taken together, circadian factors shape the diurnal oscillation of innate and adaptive immunity. Among them, GCs participate in the circadian rhythm of innate and adaptive immunity by positive and negative effects.
Asunto(s)
Inmunidad Adaptativa/fisiología , Ritmo Circadiano/fisiología , Citocinas/biosíntesis , Glucocorticoides/fisiología , Inmunidad Innata/fisiología , Receptores de Citocinas/biosíntesis , Inmunidad Adaptativa/genética , Animales , Asma/genética , Asma/inmunología , Asma/fisiopatología , Linfocitos B/inmunología , Quimiotaxis de Leucocito/inmunología , Quimiotaxis de Leucocito/fisiología , Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/genética , Ritmo Circadiano/inmunología , Citocinas/genética , Regulación de la Expresión Génica/efectos de los fármacos , Glucocorticoides/farmacología , Humanos , Hipersensibilidad/genética , Hipersensibilidad/inmunología , Hipersensibilidad/fisiopatología , Inmunidad Innata/genética , Memoria Inmunológica/efectos de los fármacos , Infecciones/genética , Infecciones/inmunología , Infecciones/fisiopatología , Ratones , Modelos Inmunológicos , Receptores CXCR4/biosíntesis , Receptores CXCR4/genética , Receptores de Citocinas/genética , Receptores de Interleucina-7/biosíntesis , Receptores de Interleucina-7/genética , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunologíaRESUMEN
Modern society characterized by a 24/7 lifestyle leads to misalignment between environmental cycles and endogenous circadian rhythms. Persisting circadian misalignment leads to deleterious effects on health and healthspan. However, the underlying mechanism remains not fully understood. Here, we subjected adult, wild-type mice to distinct chronic jet-lag paradigms, which showed that long-term circadian misalignment induced significant early mortality. Non-biased RNA sequencing analysis using liver and kidney showed marked activation of gene regulatory pathways associated with the immune system and immune disease in both organs. In accordance, we observed enhanced steatohepatitis with infiltration of inflammatory cells. The investigation of senescence-associated immune cell subsets from the spleens and mesenteric lymph nodes revealed an increase in PD-1+CD44high CD4 T cells as well as CD95+GL7+ germinal center B cells, indicating that the long-term circadian misalignment exacerbates immune senescence and consequent chronic inflammation. Our results underscore immune homeostasis as a pivotal interventional target against clock-related disorders.