RESUMEN
Malignancy can be suppressed by the immune system. However, the classes of immunosurveillance responses and their mode of tumor sensing remain incompletely understood. Here, we show that although clear cell renal cell carcinoma (ccRCC) was infiltrated by exhaustion-phenotype CD8+ T cells that negatively correlated with patient prognosis, chromophobe RCC (chRCC) had abundant infiltration of granzyme A-expressing intraepithelial type 1 innate lymphoid cells (ILC1s) that positively associated with patient survival. Interleukin-15 (IL-15) promoted ILC1 granzyme A expression and cytotoxicity, and IL-15 expression in chRCC tumor tissue positively tracked with the ILC1 response. An ILC1 gene signature also predicted survival of a subset of breast cancer patients in association with IL-15 expression. Notably, ILC1s directly interacted with cancer cells, and IL-15 produced by cancer cells supported the expansion and anti-tumor function of ILC1s in a murine breast cancer model. Thus, ILC1 sensing of cancer cell IL-15 defines an immunosurveillance mechanism of epithelial malignancies.
Asunto(s)
Neoplasias de la Mama , Interleucina-15/metabolismo , Animales , Neoplasias de la Mama/genética , Linfocitos T CD8-positivos , Femenino , Granzimas , Humanos , Inmunidad Innata , Linfocitos , RatonesRESUMEN
Fibroblastic reticular cells (FRCs) of secondary lymphoid organs form distinct niches for interaction with hematopoietic cells. We found here that production of the cytokine IL-15 by FRCs was essential for the maintenance of group 1 innate lymphoid cells (ILCs) in Peyer's patches and mesenteric lymph nodes. Moreover, FRC-specific ablation of the innate immunological sensing adaptor MyD88 unleashed IL-15 production by FRCs during infection with an enteropathogenic virus, which led to hyperactivation of group 1 ILCs and substantially altered the differentiation of helper T cells. Accelerated clearance of virus by group 1 ILCs precipitated severe intestinal inflammatory disease with commensal dysbiosis, loss of intestinal barrier function and diminished resistance to colonization. In sum, FRCs act as an 'on-demand' immunological 'rheostat' by restraining activation of group 1 ILCs and thereby preventing immunopathological damage in the intestine.
Asunto(s)
Citrobacter rodentium/inmunología , Infecciones por Coronavirus/inmunología , Infecciones por Enterobacteriaceae/inmunología , Fibroblastos/inmunología , Interleucina-15/metabolismo , Linfocitos/inmunología , Virus de la Hepatitis Murina/inmunología , Animales , Células Cultivadas , Inmunidad Innata , Ganglios Linfáticos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Ganglios Linfáticos Agregados/patología , Células TH1/inmunología , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismoRESUMEN
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
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
Recently, considerable attention has been directed toward innate-like T cells (ITCs) and innate lymphoid cells (ILCs) owing to their indispensable contributions to immune responses, tissue homeostasis, and inflammation. Innate-like T cells include NKT cells, MAIT cells, and γδ T cells, whereas ILCs include NK cells, type 1 ILCs (ILC1s), type 2 ILCs (ILC2s), and type 3 ILCs (ILC3s). Many of these ITCs and ILCs are distributed to specific tissues and remain tissue-resident, while others, such as NK cells and some γδ T cells, circulate through the bloodstream. Nevertheless, recent research has shed light on novel subsets of innate immune cells that exhibit characteristics intermediate between tissue-resident and circulating states under normal and pathological conditions. The local microenvironment frequently influences the development, distribution, and function of these innate immune cells. This review aims to consolidate the current knowledge on the functional heterogeneity of ITCs and ILCs, shaped by local environmental cues, with particular emphasis on IL-15, which governs the activities of the innate immune cells involved in type 1 immune responses.
Asunto(s)
Inmunidad Innata , Linfocitos , Humanos , Células Asesinas Naturales , InflamaciónRESUMEN
Lymphoid organs consist of immune cells and stromal cells. The stromal cells produce various cytokines that support the development, maintenance, and response of the immune cells. IL-7 and IL-15 are the major cytokines produced by stromal cells and are essential for the development and maintenance of lymphocytes and innate lymphoid cells (ILCs). In addition, IL-7 is indispensable for the organogenesis of lymphoid organs. However, because the amount of these two cytokines is relatively low, it has been difficult to directly detect their expression. Recently, several groups succeeded in establishing IL-7 and IL-15 reporter mouse lines. As expected, IL-7 and IL-15 were detected in mesenchymal stromal cells in the bone marrow and lymph nodes and in epithelial cells in the thymus. Furthermore, IL-7 and IL-15 were differentially expressed in lymphatic endothelial cells and blood endothelial cells, respectively. In addition to their expression, many groups have analyzed the local functions of IL-7 and IL-15 by using cell-type-specific knockout mice. From these experiments, CXCL12-expressing mesenchymal stromal cells were identified as the major niche for early B cell precursors. Single-cell RNA sequencing (scRNA-seq) analysis has revealed different subpopulations of stromal cells in the lymphoid organs, including those that express both IL-7 and IL-15. Future research is still needed to elucidate which stromal cells serve as the niche for the early precursors of ILCs and NK cells in the bone marrow.
Asunto(s)
Interleucina-15 , Interleucina-7 , Animales , Células Endoteliales , Inmunidad Innata , Interleucina-15/genética , Interleucina-7/genética , Células Asesinas Naturales , RatonesRESUMEN
Lymph nodes (LNs) are secondary lymphoid organs that function as the first line of defense against invasive foreign substances. Within the LNs, different types of immune cells are strategically localized to induce immune responses efficiently. Such a sophisticated tissue structure is a complex of functionally specialized niches, constructed by a variety of fibroblastic stromal cells. Elucidating the characteristics and functions of the niches and stromal cells will facilitate comprehension of the immune response induced in the LNs. Three recent studies offered novel insights into specialized stromal cells. In our discussion of these surprisingly diverse stromal cells, we will integrate information from these studies to improve knowledge about the structure and niches of LN.
Asunto(s)
Ganglios Linfáticos , Células del Estroma , InmunidadRESUMEN
TCR signaling is required for homeostasis of naive αß T cells. However, whether such a signal is necessary for γδ T cell homeostasis in the periphery remains unknown. In this study, we present evidence that a portion of Vγ2+ γδ T cells, one of the major γδ T cell subsets in the secondary lymphoid organs, requires TCR signaling for homeostasis. To attenuate γδTCR signals, we generated mice lacking Eγ4 (Eγ4-/-), an enhancer located at the 3'-most end of the TCRγ locus. Overall, we found that in thymus, Eγ4 loss altered V-J rearrangement, chromatin accessibility, and transcription of the TCRγ locus in a distance-dependent manner. Vγ2+ γδ T cells in Eγ4-/- mice developed normally both fetal and adult mouse thymi but were relatively reduced in number in spleen and lymph nodes. Although Vγ2 TCR transcription decreased in all subpopulations of Eγ4-/- mice, the number of Vγ2+ γδ T cells decreased and TCR signaling was attenuated only in the innate-like CD27+CD45RBhigh subpopulation in peripheral lymphoid organs. Consistently, CD27+CD45RBhigh Vγ2+ γδ T cells from Eγ4-/- mice transferred into Rag2-deficient mice were not efficiently recovered, suggesting that continuous TCR signaling is required for their homeostasis. Finally, CD27+CD45RBhigh Vγ2+ γδ T cells from Eγ4-/- mice showed impaired TCR-induced activation and antitumor responses. These results suggest that normal homeostasis of innate-like CD27+CD45RBhigh Vγ2+ γδ T cells in peripheral lymphoid organs requires TCR signaling.
Asunto(s)
Centro Germinal/inmunología , Ganglios Linfáticos/inmunología , Tejido Linfoide/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Subgrupos de Linfocitos T/inmunología , Linfocitos T/inmunología , Animales , Células Cultivadas , Elementos de Facilitación Genéticos/genética , Homeostasis , Inmunidad Innata , Antígenos Comunes de Leucocito/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Tolerancia Periférica , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Transducción de Señal , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/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
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
The IL-7R plays critical roles in lymphocyte development and homeostasis. Although IL-7R expression is strictly regulated during lymphocyte differentiation and the immune response, little is known regarding its in vivo regulation. To address this issue, we established a mouse line with targeted deletion of the conserved non-coding sequence 1 (CNS1) element found 3.6 kb upstream of the IL-7Rα promoter. We report that IL-7Rα is expressed normally on T and B cells in thymus and bone marrow of CNS1(-/-) mice except for in regulatory T cells. In contrast, these mice show reduced IL-7Rα expression in conventional CD4 and CD8 T cells as well as regulatory T, NKT, and γδ T cells in the periphery. CD4 T cells of CNS1(-/-) mice showed IL-7Rα upregulation in the absence of growth factors and IL-7Rα downregulation by IL-7 or TCR stimulation, although the expression levels were lower than those in control mice. Naive CD4 and CD8 T cells of CNS1(-/-) mice show attenuated survival by culture with IL-7 and reduced homeostatic proliferation after transfer into lymphopenic hosts. CNS1(-/-) mice exhibit impaired maintenance of Ag-stimulated T cells. Furthermore, IL-7Rα upregulation by glucocorticoids and TNF-α was abrogated in CNS1(-/-) mice. This work demonstrates that the CNS1 element controls IL-7Rα expression and maintenance of peripheral T cells, suggesting differential regulation of IL-7Rα expression between central and peripheral lymphoid organs.
Asunto(s)
Linfocitos T CD4-Positivos/citología , Linfocitos T CD8-positivos/citología , Elementos de Facilitación Genéticos , Subunidad alfa del Receptor de Interleucina-7/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Proliferación Celular/genética , Células Cultivadas , Dexametasona/farmacología , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Subunidad alfa del Receptor de Interleucina-7/biosíntesis , Activación de Linfocitos/inmunología , Ratones , Ratones Noqueados , Regiones Promotoras Genéticas/genética , Eliminación de Secuencia/genética , Transducción de Señal/inmunología , Transcripción Genética/genética , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
IL-15 is a cytokine critical for development, maintenance, and response of T cells, natural killer (NK) cells, NK T cells, and dendritic cells. However, the identity and distribution of IL-15-expressing cells in lymphoid organs are not well understood. To address these questions, we established and analyzed IL-15-CFP knock-in mice. We found that IL-15 was highly expressed in thymic medulla, and medullary thymic epithelial cells with high MHC class II expression were the major source of IL-15. In bone marrow, IL-15 was detected primarily in VCAM-1(+)PDGFRß(+)CD31(-)Sca-1(-) stromal cells, which corresponded to previously described CXCL12-abundant reticular cells. In lymph nodes, IL-15-expressing cells were mainly distributed in the T-cell zone and medulla. IL-15 was expressed in some fibroblastic reticular cells and gp38(-)CD31(-) double-negative stromal cells in the T-cell zone. Blood endothelial cells, including all high endothelial venules, also expressed high IL-15 levels in lymph nodes, whereas lymphatic endothelial cells (LECs) lacked IL-15 expression. In spleen, IL-15 was expressed in VCAM-1(+) stromal cells, where its expression increased as mice aged. Finally, IL-15 expression in blood and LECs of peripheral lymphoid organs significantly increased in LPS-induced inflammation. Overall, we have identified and characterized several IL-15-expressing cells in primary and secondary lymphoid organs, providing a unique perspective of IL-15 niche in immune microenvironment. This study also suggests that some stromal cells express IL-7 and IL-15 differentially and suggests a way to functionally classify different stromal cell subsets.
Asunto(s)
Interleucina-15/metabolismo , Tejido Linfoide/metabolismo , Envejecimiento/inmunología , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Técnicas de Sustitución del Gen , Inflamación/patología , Lipopolisacáridos/farmacología , Ganglios Linfáticos/citología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/metabolismo , Tejido Linfoide/citología , Tejido Linfoide/efectos de los fármacos , Mesodermo/citología , Mesodermo/efectos de los fármacos , Ratones , Membrana Mucosa/citología , Membrana Mucosa/efectos de los fármacos , Membrana Mucosa/metabolismo , Bazo/citología , Bazo/crecimiento & desarrollo , Bazo/metabolismo , Células del Estroma/citología , Células del Estroma/efectos de los fármacos , Células del Estroma/metabolismo , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Timo/citología , Timo/efectos de los fármacos , Timo/metabolismoRESUMEN
Invariant natural killer T (iNKT) cells are a distinct subpopulation of innate-like T lymphocytes. They are characterized by semi-invariant T cell receptors (TCRs) that recognize both self and foreign lipid antigens presented by CD1d, a non-polymorphic MHC class I-like molecule. iNKT cells play a critical role in stimulating innate and adaptive immune responses, providing an effective defense against infections and cancers, while also contributing to chronic inflammation. The functions of iNKT cells are specific to their location, ranging from lymphoid to non-lymphoid tissues, such as the thymus, lung, liver, intestine, and adipose tissue. This review aims to provide insights into the heterogeneity of development and function in iNKT cells. First, we will review the expression of master transcription factors that define subsets of iNKT cells and their production of effector molecules such as cytokines and granzymes. In this article, we describe the gene expression profiles contributing to the kinetics, distribution, and cytotoxicity of iNKT cells across different tissue types. We also review the impact of cytokine production in distinct immune microenvironments on iNKT cell heterogeneity, highlighting a recently identified circulating iNKT cell subset. Additionally, we explore the potential of exploiting iNKT cell heterogeneity to create potent immunotherapies for human cancers in the future.
Asunto(s)
Células T Asesinas Naturales , Neoplasias , Humanos , Señales (Psicología) , Tejido Adiposo , Membrana Celular , Microambiente TumoralRESUMEN
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.