RESUMO
CD4+ T helper 17 (TH17) cells protect barrier tissues but also trigger autoimmunity. The mechanisms behind these opposing processes remain unclear. Here, we found that the transcription factor EGR2 controlled the transcriptional program of pathogenic TH17 cells in the central nervous system (CNS) but not that of protective TH17 cells at barrier sites. EGR2 was significantly elevated in myelin-reactive CD4+ T cells from patients with multiple sclerosis and mice with autoimmune neuroinflammation. The EGR2 transcriptional program was intricately woven within the TH17 cell transcriptional regulatory network and showed high interconnectivity with core TH17 cell-specific transcription factors. Mechanistically, EGR2 enhanced TH17 cell differentiation and myeloid cell recruitment to the CNS by upregulating pathogenesis-associated genes and myelomonocytic chemokines. T cell-specific deletion of Egr2 attenuated neuroinflammation without compromising the host's ability to control infections. Our study shows that EGR2 regulates tissue-specific and disease-specific functions in pathogenic TH17 cells in the CNS.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Camundongos , Diferenciação Celular , Sistema Nervoso Central , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias , Células Th1 , Células Th17 , Fatores de Transcrição , Virulência , HumanosRESUMO
In the version of this article initially published, in second paragraph of the second subsection of Results ('Peripheral licensing of CD4+ TH17 cells in Tbx21-/- hosts'), the figure citation ('Fig. 1c') in the sentence that begins "In addition to" was incorrect. The correct citation is 'Fig. 1d'.
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The transcription factor T-bet has been associated with increased susceptibility to systemic and organ-specific autoimmunity, but the mechanism by which T-bet expression promotes neuroinflammation remains unknown. In this study, we demonstrate a cardinal role of T-bet-dependent NKp46+ innate lymphoid cells (ILCs) in the initiation of CD4+ TH17-mediated neuroinflammation. Loss of T-bet specifically in NKp46+ ILCs profoundly impaired the ability of myelin-reactive TH17 cells to invade central nervous system (CNS) tissue and protected the mice from autoimmunity. T-bet-dependent NKp46+ ILCs localized in the meninges and acted as chief coordinators of meningeal inflammation by inducing the expression of proinflammatory cytokines, chemokines and matrix metalloproteinases, which together facilitated T cell entry into CNS parenchyma. Our findings uncover a detrimental role of T-bet-dependent NKp46+ ILCs in the development of CNS autoimmune disease.
Assuntos
Imunidade Inata , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Animais , Biomarcadores , Movimento Celular/genética , Movimento Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Expressão Gênica , Imunofenotipagem , Camundongos , Camundongos Knockout , Bainha de Mielina/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Proteínas com Domínio T , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
In this issue of Immunity, Iwata et al. (2017) report that the transcription factor T-bet acts as a selective repressor of the type I interferon (IFN) transcriptional program in response to IFN-γ signaling.
Assuntos
Interferon gama/imunologia , Proteínas com Domínio T , Humanos , Fatores de TranscriçãoRESUMO
Once alerted to the presence of a pathogen, activated CD4+ T cells initiate distinct gene expression programs that produce multiple functionally specialized T helper (Th) subsets. The cytokine milieu present at the time of antigen encounter instructs CD4+ T cells to differentiate into interferon-(IFN)-γ-producing Th1 cells, interleukin-(IL)-4-producing Th2 cells, IL-17-producing Th17 cells, follicular T helper (Tfh) cells, or regulatory T (Treg) cells. In each of these Th cell subsets, a single transcription factor has been identified as a critical regulator of its specialized differentiation program. In this context, the expression of the "master regulator" is necessary and sufficient to activate lineage-specific genes while restricting the gene expression program of alternative Th fates. Thus, the transcription factor T-bet controls Th1 differentiation program, while the development of Th2, Th17, Tfh, and Treg cells is dependent on transcription factors GATA3, RORγt, Bcl6, and Foxp3, respectively. Nevertheless, master regulators or, more precisely, lineage-defining transcription factors do not function in isolation. In fact, they interact with a complex network of transcription factors, orchestrating cell lineage specification programs. In this review, we discuss the concept of the combinatorial interactions of key transcription factors in determining helper T cell identity. Additionally, lineage-defining transcription factors have well-established functions beyond their role in CD4+ Th subsets. They play critically important functions at distinct stages during T cell development in the thymus and they control the development of innate lymphoid cells (ILCs) in the bone marrow. In tracking the journey of T cells traversing from the thymus to the periphery and during the immune response, we discuss in broad terms developmental stage and context-dependent functions of lineage-defining transcription factors in regulating specification programs of innate and adaptive lymphocytes.
Assuntos
Imunidade Inata , Linfócitos T Reguladores , Linhagem da Célula/genética , Regulação da Expressão Gênica , Células Th17RESUMO
Signal tranducer and activator of transcription 5 (STAT5) plays a critical role in mediating cellular responses following cytokine stimulation. STAT proteins critically signal via the formation of dimers, but additionally, STAT tetramers serve key biological roles, and we previously reported their importance in T and natural killer (NK) cell biology. However, the role of STAT5 tetramerization in autoimmune-mediated neuroinflammation has not been investigated. Using the STAT5 tetramer-deficient Stat5a-Stat5b N-domain double knockin (DKI) mouse strain, we report here that STAT5 tetramers promote the pathogenesis of experimental autoimmune encephalomyelitis (EAE). The mild EAE phenotype observed in DKI mice correlates with the impaired extravasation of pathogenic T-helper 17 (Th17) cells and interactions between Th17 cells and monocyte-derived cells (MDCs) in the meninges. We further demonstrate that granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated STAT5 tetramerization regulates the production of CCL17 by MDCs. Importantly, CCL17 can partially restore the pathogenicity of DKI Th17 cells, and this is dependent on the activity of the integrin VLA-4. Thus, our study reveals a GM-CSF-STAT5 tetramer-CCL17 pathway in MDCs that promotes autoimmune neuroinflammation.
Assuntos
Doenças Autoimunes/metabolismo , Doenças Neuroinflamatórias/metabolismo , Fator de Transcrição STAT5 , Animais , Quimiocina CCL17/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Macrófagos/metabolismo , Camundongos , Multimerização Proteica , Fator de Transcrição STAT5/química , Fator de Transcrição STAT5/metabolismo , Células Th17/metabolismoRESUMO
The activation of immune-defense mechanisms in response to a microbial attack must be robust and appropriately tailored to fight particular types of pathogens. Infection with intracellular microorganisms elicits a type 1 inflammatory response characterized by mobilization of T helper type 1 (T(H)1) cells to the site of infection, where they are responsible for the recruitment and activation of macrophages. At the center of the type 1 inflammatory response is the transcription factor T-bet, a critical regulator of the T(H)1 differentiation program. T-bet induces the production of interferon-γ (IFN-γ) and orchestrates the T(H)1 cell-migratory program by regulating the expression of chemokines and chemokine receptors. However, tight regulation of the type 1 inflammatory response is essential for the prevention of immunopathology and the development of organ-specific autoimmunity. In this review, we discuss how T-bet expression drives autoaggressive and inflammatory processes and how its function in vivo must be delicately balanced to avoid disease.
Assuntos
Doenças Transmissíveis/imunologia , Proteínas com Domínio T/imunologia , Animais , Asma/imunologia , Doenças Autoimunes/imunologia , Humanos , Imunidade Celular , Inflamação/imunologia , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Camundongos , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
Overactive responses by interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) are tightly linked to the development of autoimmunity, yet the factors that negatively regulate the differentiation of this lineage remain unknown. Here we report that the transcription factor T-bet suppressed development of the T(H)17 cell lineage by inhibiting transcription of Rorc (which encodes the transcription factor RORγt). T-bet interacted with the transcription factor Runx1, and this interaction blocked Runx1-mediated transactivation of Rorc. T-bet Tyr304 was required for formation of the T-bet-Runx1 complex, for blockade of Runx1 activity and for inhibition of the T(H)17 differentiation program. Our data reinforce the idea of master regulators that shape immune responses by simultaneously activating one genetic program while silencing the activity of competing regulators in a common progenitor cell.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Proteínas com Domínio T/metabolismo , Células Th17/metabolismo , Animais , Diferenciação Celular/genética , Linhagem da Célula/genética , Células Cultivadas , Subunidade alfa 2 de Fator de Ligação ao Core/imunologia , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Ligação Proteica/genética , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Células Th17/imunologia , Células Th17/patologiaRESUMO
Very little is known about the transcription factor network that regulates the development of intestinal intraepithelial lymphocytes (IELs). In this issue of Immunity, Klose et al. (2014b) and Reis et al. (2014) demonstrate an essential role for T-bet in regulating the CD8αα IEL differentiation program.
Assuntos
Subunidade alfa 3 de Fator de Ligação ao Core/imunologia , Proteínas com Domínio T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , AnimaisRESUMO
T helper 17 (Th17) cells can give rise to interleukin-17A (IL-17A)- and interferon (IFN)-γ-double-producing cells that are implicated in development of autoimmune diseases. However, the molecular mechanisms that govern generation of IFN-γ-producing Th17 cells are unclear. We found that coexpression of the Th1 and Th17 cell master transcription factors, T-bet and retinoid-related orphan receptor gamma-t (RORγt), respectively, did not generate Th cells with robust IL-17 and IFN-γ expression. Instead, development of IFN-γ-producing Th17 cells required T-bet and Runx1 or Runx3. IL-12-stimulated Th17 cells upregulated Runx1, which bound to the Ifng locus in a T-bet-dependent manner. Reciprocally, T-bet or Runx1 deficiency or inhibition of Runx transcriptional activity impaired the development of IFN-γ-producing Th17 cells during experimental autoimmune encephalomyelitis, which correlated with substantially ameliorated disease course. Thus, our studies identify a critical role for T-bet and Runx transcription factors in the generation of pathogenic IFN-γ-producing Th17 cells.
Assuntos
Subunidades alfa de Fatores de Ligação ao Core/metabolismo , Interferon gama/biossíntese , Proteínas com Domínio T/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Animais , Diferenciação Celular , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Subunidades alfa de Fatores de Ligação ao Core/genética , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Expressão Gênica , Loci Gênicos , Interferon gama/genética , Camundongos , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ligação Proteica , Proteínas com Domínio T/genética , Células Th1/citologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/citologiaRESUMO
The common γ-chain (γc) plays a central role in signaling by IL-2 and other γc-dependent cytokines. Here we report that activated T cells produce an alternatively spliced form of γc mRNA that results in protein expression and secretion of the γc extracellular domain. The soluble form of γc (sγc) is present in serum and directly binds to IL-2Rß and IL-7Rα proteins on T cells to inhibit cytokine signaling and promote inflammation. sγc suppressed IL-7 signaling to impair naive T cell survival during homeostasis and exacerbated Th17-cell-mediated inflammation by inhibiting IL-2 signaling upon T cell activation. Reciprocally, the severity of Th17-cell-mediated inflammatory diseases was markedly diminished in mice lacking sγc. Thus, sγc expression is a naturally occurring immunomodulator that regulates γc cytokine signaling and controls T cell activation and differentiation.
Assuntos
Processamento Alternativo/imunologia , Encefalomielite Autoimune Experimental/imunologia , Cadeias gama de Imunoglobulina/imunologia , Inflamação/imunologia , Células Th17/imunologia , Animais , Autoimunidade , Diferenciação Celular/imunologia , Proliferação de Células , Sobrevivência Celular/imunologia , Cadeias gama de Imunoglobulina/sangue , Cadeias gama de Imunoglobulina/genética , Imunomodulação , Subunidade beta de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-5/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica/imunologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Transdução de Sinais/imunologiaRESUMO
Integrin CD103 mediates the adhesion and tissue retention of T cells by binding to E-cadherin which is abundant on epithelial cells. Notably, CD103 is highly expressed on CD8 T cells but conspicuously absent on most CD4 T cells. The mechanism controlling such lineage-specific expression of CD103 remains unclear. Using a series of genetically engineered mouse models, here, we demonstrate that the regulatory mechanism of CD103 expression is distinct between CD4 and CD8 T cells, and that the transcription factor Runx3 plays an important but not an essential role in this process. We further found that the availability of integrin ß7 which heterodimerizes with CD103 was necessary but also constrained the surface expression of CD103. Notably, the forced surface expression of CD103 did not significantly alter the thymic development of conventional T cells but severely impaired the generation of MHC-II-restricted TCR transgenic T cells, revealing previously unappreciated aspects of CD103 in the selection and maturation of CD4 T cells. Unlike its effect on CD4 T cell development, however, CD103 overexpression did not significantly affect CD4 T cells in peripheral tissues. Moreover, the frequency and number of CD4 T cells in the small intestine epithelium did not increase even though E-cadherin is highly expressed in this tissue. Collectively, these results suggest that most mature CD4 T cells are refractory to the effects of CD103 expression, and that they presumably utilize CD103-independent pathways to control their tissue retention and residency.
Assuntos
Antígenos CD/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Cadeias alfa de Integrinas/metabolismo , Animais , Caderinas/metabolismo , Feminino , Cadeias beta de Integrinas/metabolismo , Mucosa Intestinal/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos TransgênicosRESUMO
The cross-talk between the microbiota and the immune system plays a fundamental role in the control of host physiology. However, the tissue-specific factors controlling this dialogue remain poorly understood. Here we demonstrate that T cell responses to commensal colonization are associated with the development of organized cellular clusters within the skin epithelium. These organized lymphocyte clusters are surrounded by keratinocytes expressing a discrete program associated with antigen presentation and antimicrobial defense. Notably, IL-22-mediated keratinocyte-intrinsic MHC class II expression was required for the selective accumulation of commensal-induced IFN-γ, but not IL-17A-producing CD4+ T cells within the skin. Taking these data together, this work uncovers an unexpected role for MHC class II expression by keratinocytes in the control of homeostatic type 1 responses to the microbiota. Our findings have important implications for the understanding of the tissue-specific rules governing the dialogue between a host and its microbiota.
Assuntos
Epiderme/microbiologia , Antígenos de Histocompatibilidade Classe II/biossíntese , Interações entre Hospedeiro e Microrganismos/imunologia , Queratinócitos/imunologia , Microbiota/imunologia , Células Th1/imunologia , Animais , Apresentação de Antígeno , Candida albicans/imunologia , Epiderme/imunologia , Genes MHC da Classe II , Interferon gama/biossíntese , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Quimera por Radiação , Organismos Livres de Patógenos Específicos , Staphylococcus aureus/imunologia , Staphylococcus epidermidis/imunologia , Simbiose , Células Th1/metabolismoRESUMO
Prevention programs are a key method to reduce the prevalence and impact of mental health disorders in childhood and adolescence. Caregiver participation engagement (CPE), which includes caregiver participation in sessions as well as follow-through with homework plans, is theorized to be an important component in the effectiveness of these programs. This systematic review aims to (1) describe the terms used to operationalize CPE and the measurement of CPE in prevention programs, (2) identify factors associated with CPE, (3) examine associations between CPE and outcomes, and (4) explore the effects of strategies used to enhance CPE. Thirty-nine articles representing 27 unique projects were reviewed. Articles were included if they examined CPE in a program that focused to some extent on preventing child mental health disorders. There was heterogeneity in both the terms used to describe CPE and the measurement of CPE. The majority of projects focused on assessment of caregiver home practice. There were no clear findings regarding determinants of CPE. With regard to the impact of CPE on program outcomes, higher levels of CPE predicted greater improvements in child and caregiver outcomes, as well as caregiver-child relationship quality. Finally, a small number of studies found that motivational and behavioral strategies (e.g., reinforcement, appointment reminders) were successful in promoting CPE. This review highlights the importance of considering CPE when developing, testing, and implementing prevention programs for child mental health disorders. Increased uniformity is needed in the measurement of CPE to facilitate a better understanding of determinants of CPE. In addition, the field would benefit from further evaluating strategies to increase CPE as a method of increasing the potency of prevention programs.
Assuntos
Cuidadores , Saúde Mental , Adolescente , Família , HumanosRESUMO
OBJECTIVES: Language brokering (LB) often occurs in public places, putting youth who broker at risk for experiencing discrimination while engaging in brokering. Guided by the risk and resilience theoretical framework, the present study goals were twofold: (a) to examine the association between discrimination and LB, and (b) to explore moderating abilities of ethnic identity and family dynamics. METHOD: Data were collected from 458 young adults (Mage = 21.36, 80% female). Participants were from a diverse region in the United States, and a majority of them self-identified as Latino (66.2%). Participants were invited to complete a one-time online survey about their LB and family experiences. RESULTS: We found that discrimination was negatively associated with LB for these young people. Specifically, discrimination was related to higher LB burden and higher LB role reversal, and lower LB efficacy. In addition, we found that ethnic-racial identity (ERI) acted as a moderator of LB role reversal against discrimination, and that negative family dynamics moderated the association between discrimination and LB. Positive family dynamics were not successful in buffering against negative effects of discrimination. CONCLUSIONS: Our findings indicate that young people who broker seem to be negatively impacted by discrimination. The effects of discrimination on LB role reversal could be alleviated by strong ERI; however, the same is not true for LB burden and LB efficacy. Furthermore, negative family dynamics exacerbated the negative effects of discrimination on LB, and positive family dynamics did not serve as a buffer against discrimination. Implications for those working with language brokers are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
RESUMO
The influence of signals transmitted by the phosphatase calcineurin and the transcription factor NFAT on the development and function of natural killer T (NKT) cells is unclear. In this report, we demonstrate that the transcription factor early growth response 2 (Egr2), a target gene of NFAT, was specifically required for the ontogeny of NKT cells but not that of conventional CD4(+) or CD8(+) T cells. NKT cells developed normally in the absence of Egr1 or Egr3, which suggests that Egr2 is a specific regulator of NKT cell differentiation. We found that Egr2 was important in the selection, survival and maturation of NKT cells. Our findings emphasize the importance of the calcineurin-NFAT-Egr2 pathway in the development of the NKT lymphocyte lineage.
Assuntos
Diferenciação Celular , Proteína 2 de Resposta de Crescimento Precoce/metabolismo , Fatores de Transcrição NFATC/metabolismo , Células T Matadoras Naturais/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Calcineurina/metabolismo , Células Cultivadas , Proteína 2 de Resposta de Crescimento Precoce/genética , Proteína 2 de Resposta de Crescimento Precoce/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/imunologiaRESUMO
The speed of impulse transmission is critical for optimal neural circuit function, but it is unclear how the appropriate conduction velocity is established in individual axons. The velocity of impulse transmission is influenced by the thickness of the myelin sheath and the morphology of electrogenic nodes of Ranvier along axons. Here we show that myelin thickness and nodal gap length are reversibly altered by astrocytes, glial cells that contact nodes of Ranvier. Thrombin-dependent proteolysis of a cell adhesion molecule that attaches myelin to the axon (neurofascin 155) is inhibited by vesicular release of thrombin protease inhibitors from perinodal astrocytes. Transgenic mice expressing a dominant-negative fragment of VAMP2 in astrocytes, to reduce exocytosis by 50%, exhibited detachment of adjacent paranodal loops of myelin from the axon, increased nodal gap length, and thinning of the myelin sheath in the optic nerve. These morphological changes alter the passive cable properties of axons to reduce conduction velocity and spike-time arrival in the CNS in parallel with a decrease in visual acuity. All effects were reversed by the thrombin inhibitor Fondaparinux. Similar results were obtained by viral transfection of tetanus toxin into astrocytes of rat corpus callosum. Previously, it was unknown how the myelin sheath could be thinned and the functions of perinodal astrocytes were not well understood. These findings describe a form of nervous system plasticity in which myelin structure and conduction velocity are adjusted by astrocytes. The thrombin-dependent cleavage of neurofascin 155 may also have relevance to myelin disruption and repair.
Assuntos
Astrócitos/fisiologia , Bainha de Mielina/fisiologia , Animais , Axônios/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Bainha de Mielina/metabolismo , Fibras Nervosas Mielinizadas/fisiologia , Condução Nervosa/fisiologia , Neuroglia/metabolismo , Nervo Óptico/metabolismo , Nós Neurofibrosos/metabolismo , Relação Estrutura-Atividade , Trombina , Proteína 2 Associada à Membrana da VesículaRESUMO
OBJECTIVES: This study examined family dynamics as a moderator of the association between discrimination and both depression and life satisfaction for Latino youth. Specifically, we hypothesized that discrimination would have a negative impact on depression and life satisfaction. We also hypothesized that negative family dynamics would compound the negative impact of discrimination, whereas positive family dynamics would buffer against the impact of discrimination on depression and life satisfaction. METHOD: Participants were 229 Latino youth (Mage = 22.40, SD = 2.46, % female = 81.7) from a diverse region who completed measures of perceived discrimination, depressive symptoms, life satisfaction, and family relationship dynamics. Regression models were used to test both direct associations and moderation (i.e., interaction effects) between these variables. RESULTS: Findings indicated that negative aspects of family dynamics marginally exacerbated the link between discrimination and depression and life satisfaction, and were also directly associated with these outcomes. Family positivity significantly moderated the association between discrimination and both depression and life satisfaction. However, positive aspects of family dynamics were only associated with more positive outcomes when discrimination was minimal to absent. CONCLUSIONS: Family dynamics moderated the association between discrimination and both depression and life satisfaction in Latino youth. However, family dynamics did not appear sufficient to buffer against the negative impact of discrimination, suggesting that even positive and cohesive families cannot buffer youth from discrimination. Marginal findings suggest that negative family dynamics compound the negative impact of discrimination. Implications for improving the mental health of Latino youth through targeting both discrimination and family dynamics are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Assuntos
Relações Familiares , Hispânico ou Latino , Adulto , Depressão , Feminino , Humanos , Masculino , Adulto JovemRESUMO
The transcription factor T-bet (Tbox protein expressed in T cells) is one of the master regulators of both the innate and adaptive immune responses. It plays a central role in T-cell lineage commitment, where it controls the TH1 response, and in gene regulation in plasma B-cells and dendritic cells. T-bet is a member of the Tbox family of transcription factors; however, T-bet coordinately regulates the expression of many more genes than other Tbox proteins. A central unresolved question is how T-bet is able to simultaneously recognize distant Tbox binding sites, which may be located thousands of base pairs away. We have determined the crystal structure of the Tbox DNA binding domain (DBD) of T-bet in complex with a palindromic DNA. The structure shows a quaternary structure in which the T-bet dimer has its DNA binding regions splayed far apart, making it impossible for a single dimer to bind both sites of the DNA palindrome. In contrast to most other Tbox proteins, a single T-bet DBD dimer binds simultaneously to identical half-sites on two independent DNA. A fluorescence-based assay confirms that T-bet dimers are able to bring two independent DNA molecules into close juxtaposition. Furthermore, chromosome conformation capture assays confirm that T-bet functions in the direct formation of chromatin loops in vitro and in vivo. The data are consistent with a looping/synapsing model for transcriptional regulation by T-bet in which a single dimer of the transcription factor can recognize and coalesce distinct genetic elements, either a promoter plus a distant regulatory element, or promoters on two different genes.
Assuntos
Cromatina/química , DNA/química , Genoma , Proteínas com Domínio T/química , Sequência de Aminoácidos , Animais , Sítios de Ligação , Cromatina/metabolismo , Cristalografia por Raios X , DNA/genética , DNA/metabolismo , Elementos Facilitadores Genéticos , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Sequências Repetidas Invertidas , Camundongos , Modelos Moleculares , Regiões Promotoras Genéticas , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Estrutura Quaternária de Proteína , Estrutura Secundária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Xenopus laevisRESUMO
T cells are both producers and consumers of cytokines, and autocrine cytokine signaling plays a critical role in T cell immunity. IL-15 is a homeostatic cytokine for T cells that also controls inflammatory immune responses. An autocrine role of T cell-derived IL-15, however, remains unclear. Here we examined IL-15 expression and signaling upon effector T cell differentiation in mice, and, surprisingly, found that CD4 T cells did not express IL-15. CD4 T cells lacked Il15 gene reporter activity, did not contain IL-15 transcripts, and did not produce IL-15Rα, the proprietary IL-15 receptor required for IL-15 trans-presentation. Moreover, IL-15 failed to inhibit Th17 cell differentiation and failed to generate Foxp3+ Treg cells in vitro. IL-2, which utilizes the same IL-2Rß/γc receptor complex, however, successfully did so. Exogenous IL-15 only exerted bioactivity and controlled T cell differentiation when it was trans-presented by IL-15Rα. Consequently, IL-15Rα-bound IL-15, but not free IL-15, suppressed Th17 cell differentiation and induced Treg cell generation. Collectively, these results reveal the absence of an IL-15 autocrine loop in CD4 T cells and strongly suggest that IL-15 trans-presentation by non-CD4 T cells is the primary mechanism via which IL-15 controls CD4 effector T cell differentiation.