RESUMO
Interferon regulatory factor 4 (IRF4) is a master transcription factor that regulates T helper cell (Th) differentiation. It interacts with the Basic leucine zipper transcription factor, ATF-like (BATF), depletion of which in CD4+ T cells abrogates acute graft-versus-host disease (aGVHD)-induced colitis. Here, we investigated the immune-regulatory role of Irf4 in a mouse model of MHC-mismatched bone marrow transplantation. We found that recipients of allogenic Irf4-/- CD4+ T cells developed less GVHD-related symptoms. Transcriptome analysis of re-isolated donor Irf4-/- CD4+ T helper (Th) cells, revealed gene expression profiles consistent with loss of effector T helper cell signatures and enrichment of a regulatory T cell (Treg) gene expression signature. In line with these findings, we observed a high expression of the transcription factor BTB and CNC homolog 2; (BACH2) in Irf4-/- T cells, which is associated with the formation of Treg cells and suppression of Th subset differentiation. We also found an association between BACH2 expression and Treg differentiation in patients with intestinal GVHD. Finally, our results indicate that IRF4 and BACH2 act as counterparts in Th cell polarization and immune homeostasis during GVHD. In conclusion, targeting the BACH2/IRF4-axis could help to develop novel therapeutic approaches against GVHD.
Assuntos
Colite , Doença Enxerto-Hospedeiro , Camundongos , Animais , Humanos , Colite/induzido quimicamente , Colite/genética , Linfócitos T Reguladores/metabolismo , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/metabolismoRESUMO
IRF4 knock-out cells do not differentiate properly into T helper subsets 2, 9, and 17. Compared to WT IRF4 point mutation L116R shows differentially expressed key cytokines. While amounts Th2 and Th17 cells are decreased, there is a strong induction of Th9 cells in cells carrying the L116R mutated IRF4.
Assuntos
Interleucina-9 , Células Th17 , Diferenciação Celular/genética , Citocinas/genética , Citocinas/metabolismo , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Interferons/genética , Interleucina-9/genética , Interleucina-9/metabolismo , Mutação Puntual , Células Th17/metabolismo , Células Th2/metabolismoAssuntos
Vacina BNT162 , Linfócitos T , Adulto , Anticorpos Neutralizantes , Anticorpos Antivirais , Humanos , SARS-CoV-2 , VacinaçãoRESUMO
The processes leading from disturbed B-cell development to adult B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) remain poorly understood. Here, we describe Irf4-/- mice as prone to developing BCP-ALL with age. Irf4-/- preB-I cells exhibited impaired differentiation but enhanced proliferation in response to IL-7, along with reduced retention in the IL-7 providing bone marrow niche due to decreased CXCL12 responsiveness. Thus selected, preB-I cells acquired Jak3 mutations, probably following irregular AID activity, resulting in malignant transformation. We demonstrate heightened IL-7 sensitivity due to Jak3 mutants, devise a model to explain it, and describe structural and functional similarities to Jak2 mutations often occurring in human Ph-like ALL. Finally, targeting JAK signaling with Ruxolitinib in vivo prolonged survival of mice bearing established Irf4-/- leukemia. Intriguingly, organ infiltration including leukemic meningeosis was selectively reduced without affecting blood blast counts. In this work, we present spontaneous leukemogenesis following IRF4 deficiency with potential implications for high-risk BCP-ALL in adult humans.
Assuntos
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Animais , Humanos , Camundongos , Linfócitos B , Linfoma de Burkitt/patologia , Interleucina-7/genética , Janus Quinase 3/genética , Mutação/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transdução de SinaisRESUMO
Here we compared SARS-CoV-2-specific antibody and T-cell responses between older adults (>80 years old, n = 51) and a younger control group (20-53 years old, n = 46) after receiving two doses of BNT162b2. We found that responses in older adults were generally lower, and we identified 10% low-/non-responders. After receiving a third vaccination with BNT162b2, 4 out of 5 low-/non-responders showed antibody and T-cell responses similar to those of responders after two vaccinations.
Assuntos
Anticorpos Antivirais/sangue , Vacina BNT162/imunologia , COVID-19/prevenção & controle , Imunidade Celular , Imunidade Humoral , Imunogenicidade da Vacina , SARS-CoV-2/imunologia , Adulto , Fatores Etários , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/sangue , Vacina BNT162/administração & dosagem , COVID-19/imunologia , Humanos , Imunização Secundária/métodos , Imunização Secundária/estatística & dados numéricos , Imunoglobulina G/sangue , Pessoa de Meia-Idade , Testes de Neutralização , Linfócitos T/imunologia , Adulto JovemRESUMO
Apart from the constitutive proteasome, the immunoproteasome that comprises the three proteolytic subunits LMP2, MECL-1, and LMP7 is expressed in most immune cells. In this study, we describe opposing roles for immunoproteasomes in regulating the tumor microenvironment (TME). During chronic inflammation, immunoproteasomes modulated the expression of protumorigenic cytokines and chemokines and enhanced infiltration of innate immune cells, thus triggering the onset of colitis-associated carcinogenesis (CAC) in wild-type mice. Consequently, immunoproteasome-deficient animals (LMP2/MECL-1/LMP7-null mice) were almost completely resistant to CAC development. In patients with ulcerative colitis with high risk for CAC, immunoproteasome-induced protumorigenic mediators were upregulated. In melanoma tumors, the role of immunoproteasomes is relatively unknown. We found that high expression of immunoproteasomes in human melanoma was associated with better prognosis. Similarly, our data revealed that the immunoproteasome has antitumorigenic activity in a mouse model of melanoma. The antitumor immunity against melanoma was compromised in immunoproteasome-deficient mice because of the impaired activity of CD8+ CTLs, CD4+ Th1 cells, and antigen-presenting cells. These findings show that immunoproteasomes may exert opposing roles with either pro- or antitumoral properties in a context-dependent manner.
Assuntos
Cisteína Endopeptidases/metabolismo , Melanoma Experimental/imunologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral/imunologia , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Colite/patologia , Cisteína Endopeptidases/deficiência , Cisteína Endopeptidases/genética , Citocinas/metabolismo , Feminino , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Melanoma Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexo de Endopeptidases do Proteassoma/genética , Linfócitos T Citotóxicos/metabolismoRESUMO
Liver X receptors (LXR) are transcription factors from the nuclear receptor family that are activated by oxysterols and synthetic high-affinity agonists. In this study, we assessed the antitumor effects of synthetic LXR agonist TO901317 in a murine model of syngeneic Lewis Lung carcinoma. Treatment with TO901317 inhibited tumor growth in wild-type, but not in LXR-deficient mice, indicating that the antitumor effects of the agonist depends on functional LXR activity in host cells. Pharmacologic activation of the LXR pathway reduced the intratumoral abundance of regulatory T cells (Treg) and the expression of the Treg-attracting chemokine Ccl17 by MHCIIhigh tumor-associated macrophages (TAM). Moreover, gene expression profiling indicated a broad negative impact of the LXR agonist on other mechanisms used by TAM for the maintenance of an immunosuppressive environment. In studies exploring the macrophage response to GM-CSF or IL4, activated LXR repressed IRF4 expression, resulting in subsequent downregulation of IRF4-dependent genes including Ccl17. Taken together, this work reveals the combined actions of the LXR pathway in the control of TAM responses that contribute to the antitumoral effects of pharmacologic LXR activation. Moreover, these data provide new insights for the development of novel therapeutic options for the treatment of cancer. SIGNIFICANCE: This study reveals unrecognized roles of LXR in the transcriptional control of the tumor microenvironment and suggests use of a synthetic LXR agonist as a novel therapeutic strategy to stimulate antitumor activity.
Assuntos
Benzoatos/farmacologia , Benzilaminas/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Sulfonamidas/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Macrófagos Associados a Tumor/efeitos dos fármacos , Animais , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Receptores X do Fígado/agonistas , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Células RAW 264.7 , Linfócitos T Reguladores/patologia , Transcriptoma/efeitos dos fármacos , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologiaRESUMO
We found that deletion of the final 30 amino acids of transcription factor IRF4's (interferon-regulatory factor) C-terminus creates hyperactive IRF4. When introduced into IRF4-deficient CD4+ or CD8+ T cells, more type 17 differentiation was found compared to WT IRF4. Interestingly, Th9 differentiation and Th2-linked IL-13 production were much less altered.
Assuntos
Fatores Reguladores de Interferon/genética , Mutação , Subpopulações de Linfócitos T/metabolismo , Animais , Humanos , Fatores Reguladores de Interferon/metabolismo , Subpopulações de Linfócitos T/imunologiaRESUMO
GPCR expression was intensively studied in bulk cDNA of leukocyte populations, but limited data are available with respect to expression in individual cells. Here, we show a microfluidic-based single-cell GPCR expression analysis in primary T cells, myeloid cells, and endothelial cells under naive conditions and during experimental autoimmune encephalomyelitis, the mouse model of multiple sclerosis. We found that neuroinflammation induces characteristic changes in GPCR heterogeneity and patterning, and we identify various functionally relevant subgroups with specific GPCR profiles among spinal cord-infiltrating CD4 T cells, macrophages, microglia, or endothelial cells. Using GPCRs CXCR4, S1P1, and LPHN2 as examples, we show how this information can be used to develop new strategies for the functional modulation of Th17 cells and activated endothelial cells. Taken together, single-cell GPCR expression analysis identifies functionally relevant subpopulations with specific GPCR repertoires and provides a basis for the development of new therapeutic strategies in immune disorders.