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1.
Front Immunol ; 10: 2486, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681337

RESUMO

Regulatory T cells (Tregs) are engaged in maintaining immune homeostasis and preventing autoimmunity. Treg cells include thymic Treg cells and peripheral Treg cells, both of which can suppress the immune response via multiple distinct mechanisms. The differentiation, proliferation, suppressive function and survival of Treg cells are affected by distinct energy metabolic programs. Tissue-resident Treg cells hold unique features in comparison with the lymphoid organ Treg cells. Foxp3 transcription factor is a lineage master regulator for Treg cell development and suppressive activity. Accumulating evidence indicates that the activity of Foxp3 protein is modulated by various post-translational modifications (PTMs), including phosphorylation, O-GlcNAcylation, acetylation, ubiquitylation and methylation. These modifications affect multiple aspects of Foxp3 function. In this review, we define features of Treg cells and roles of Foxp3 in Treg biology, and summarize current research in PTMs of Foxp3 protein involved in modulating Treg function. This review also attempts to define Foxp3 dimer modifications relevant to mediating Foxp3 activity and Treg suppression. Understanding Foxp3 protein features and modulation mechanisms may help in the design of rational therapies for immune diseases and cancer.

2.
Trends Immunol ; 40(10): 888-908, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31601519

RESUMO

During homeostasis, interactions between tolerogenic dendritic cells (DCs), self-reactive T cells, and T regulatory cells (Tregs) contribute to maintaining mammalian immune tolerance. In response to infection, immunogenic DCs promote the generation of proinflammatory effector T cell subsets. When complex homeostatic mechanisms maintaining the balance between regulatory and effector functions become impaired, autoimmune diseases can develop. We discuss some of the newest advances on the mechanisms of physiopathologic homeostasis that can be employed to develop strategies to restore a dysregulated immune equilibrium. Some of these designs are based on selectively activating regulators of immunity and inflammation instead of broadly suppressing these processes. Promising approaches include the use of nanoparticles (NPs) to restore Treg control over self-reactive cells, aiming to achieve long-term disease remission, and potentially to prevent autoimmunity in susceptible individuals.

3.
Nat Commun ; 10(1): 4712, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31624262

RESUMO

Immune checkpoint inhibitor (ICI) use remains a challenge in patients with solid organ allografts as most would undergo rejection. In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance. Strong granzyme B+, interferon (IFN)-γ+ CD8+ cytotoxic T cell and circulating regulatory T (Treg) cell responses were noted during allograft rejection, along with significant eosinophilia and elevated serum IL-5 and eotaxin levels. Co-treatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated Treg cell numbers in the peripheral blood were maintained. Interestingly, numbers of IFN-γ+ CD4+ T cells and serum IFN-γ levels increased with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Thus, our results indicate that sirolimus has the potential to uncouple anti-PD-1 therapy toxicity and efficacy.

4.
Mol Cancer Ther ; 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534011

RESUMO

The combination of radiation with immune-checkpoint inhibitors was reported in some cancers to have synergic effects both locally and distally. Our aim was to assess this combined therapy on both radiated and non-radiated bladder tumors and to characterize the immune landscape within the tumor microenvironment. Murine bladder cancer cells (MB49) were injected s.c. in both flanks of C57BL/6 mice. Mice were randomly assigned to the following treatments: placebo, antiPD-L1 (4 intra-peritoneal injections over 2 weeks), radiation to right flank (10Gy in two fractions), or radiation+anti-PD-L1. Tumor digestion, flow cytometry, and qPCR were performed. Log-rank analysis was used for statistical significance. Radiation+antiPD-L1 group demonstrated statistically significant slower tumor growth rate both in the radiated and non-irradiated tumors (p<0.001). Survival curves demonstrated superior survival in the combination group compared to each treatment alone (p=0.02). Flow cytometry showed increased infiltration of immuno-suppressive cells as well as cytotoxic lymphocytes (CTL) in the radiation and combination groups (p=0.04). Ratio of immunosuppressive cells to CTL shifted in favor of cytotoxic activity in the combination arm (p<0.001). The qPCR analysis revealed downregulation of immunosuppressive genes (CCL22, IL22 and IL13), as well as upregulation of markers of CTL activation (CXCL9, GZMA and GZMB) within both the radiated and distant tumors within the combination group. Combining radiation with immune checkpoint inhibitor provided better response in the radiated tumors and also the distant tumors along with a shift within the tumor microenvironment favoring cytotoxic activity. These findings demonstrate a possible abscopal effect in urothelial carcinoma with combination therapy.

5.
J Immunol ; 203(9): 2388-2400, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31554694

RESUMO

Foxp3+ regulatory T (TREG) cells are central mediators in the control of peripheral immune responses. Genome-wide transcriptional profiles show canonical signatures for Foxp3+ TREG cells, distinguishing them from Foxp3- effector T (TEFF) cells. We previously uncovered distinct mRNA translational signatures differentiating CD4+ TEFF and TREG cells through parallel measurements of cytosolic (global) and polysome-associated (translationally enhanced) mRNA levels in both subsets. We show that the mRNA encoding for the ubiquitin-specific peptidase 11 (USP11), a known modulator of TGF-ß signaling, was preferentially translated in TCR-activated TREG cells compared with conventional, murine CD4+ T cells. TGF-ß is a key cytokine driving the induction and maintenance of Foxp3 expression in T cells. We hypothesized that differential translation of USP11 mRNA endows TREG cells with an advantage to respond to TGF-ß signals. In an in vivo mouse model promoting TREG cells plasticity, we found that USP11 protein was expressed at elevated levels in stable TREG cells, whereas ectopic USP11 expression enhanced the suppressive capacity and lineage commitment of these cells in vitro and in vivo. USP11 overexpression in TEFF cells enhanced the activation of the TGF-ß pathway and promoted TREG or TH17, but not Th1, cell differentiation in vitro and in vivo, an effect abrogated by USP11 gene silencing or the inhibition of enzymatic activity. Thus, USP11 potentiates TGF-ß signaling in both TREG and TEFF cells, in turn driving increased suppressive function and lineage commitment in thymic-derived TREG cells and potentiating the TGF-ß-dependent differentiation of TEFF cells to peripherally induced TREG and TH17 cells.

6.
Front Immunol ; 10: 1532, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379810

RESUMO

The CD4+FOXP3+ regulatory T cell (Treg) subset is an indispensable mediator of immune tolerance. While high and stable expression of the transcription factor FOXP3 is considered a hallmark feature of Treg cells, our previous studies have demonstrated that the human FOXP3+ subset is functionally heterogeneous, whereby a sizeable proportion of FOXP3+ cells in healthy individuals have a diminished capacity to suppress the proliferation and cytokine production of responder cells. Notably, these non-suppressive cells are indistinguishable from suppressive Treg cells using conventional markers of human Treg. Here we investigate potential factors that underlie loss of suppressive function in human Treg cells. We show that high expression of the IL-6 family cytokine receptor subunit gp130 identifies Treg cells with reduced suppressive capacity ex vivo and in primary FOXP3+ clones. We further show that two gp130-signaling cytokines, IL-6 and IL-27, impair the suppressive capacity of human Treg cells. Finally, we show that gp130 signaling reduces the expression of the transcription factor Helios, whose expression is essential for stable Treg function. These results highlight the role of gp130 in regulating human Treg function, and suggest that modulation of gp130 signaling may serve as a potential avenue for the therapeutic manipulation of human Treg function.

7.
Sci Rep ; 9(1): 6348, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015520

RESUMO

Radical cystectomy (RC) together with bilateral pelvic lymph node dissection remains the standard treatment for muscle invasive bladder cancer (MIBC). However, radiation-based treatments such as tri-modal therapy (TMT) involving maximally performed transurethral resection of bladder tumor (TURBT), radiotherapy (XRT), and a chemosensitizer represent an attractive, less invasive alternative. Nevertheless, 25-30% of MIBC patients will experience local recurrence after TMT and half will develop metastasis. Radioresistance of tumor cells could potentially be one of the causes for local recurrence post treatment. High mobility group box-1 (HMGB1) was shown to play a role in bladder cancer radioresistance through its intracellular functions in promoting DNA damage repair and autophagy. Recently, HMGB1 was found to be passively released from irradiated tumor cells. However, less is known about the involvement of extracellular HMGB1 in impairing radiation response and its exact role in modulating the tumor immune microenvironment after XRT. We identified a novel mechanism of bladder cancer radioresistance mediated by the immunological functions of HMGB1. The combination of radiation plus extracellular HMGB1 inhibition markedly improved the radiation response of tumors and resulted in marked changes in the immune landscape. Moreover, combining radiation and HMGB1 inhibition significantly impaired tumor infiltrating MDSCs and TAMs -but not Tregs- and shifted the overall tumor immune balance towards anti-tumoral response. We conclude that extracellular HMGB1 is involved in bladder cancer radioresistance through promoting pro-tumor immune mechanisms.

8.
Front Immunol ; 10: 522, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949175

RESUMO

IL-33, a member of the IL-1 family of cytokines, was originally described in 2005 as a promoter of type 2 immune responses. However, recent evidence reveals a more complex picture. This cytokine is released locally as an alarmin upon cellular damage where innate cell types respond to IL-33 by modulating their differentiation and influencing the polarizing signals they provide to T cells at the time of antigen presentation. Moreover, the prominent expression of the IL-33 receptor, ST2, on GATA3+ T helper 2 cells (TH2) demonstrated that IL-33 could have a direct impact on T cells. Recent observations reveal that T-bet+ TH1 cells and Foxp3+ regulatory T (TREG) cells can also express the ST2 receptor, either transiently or permanently. As such, IL-33 can have a direct effect on the dynamics of T cell populations. As IL-33 release was shown to play both an inflammatory and a suppressive role, understanding the complex effect of this cytokine on T cell homeostasis is paramount. In this review, we will focus on the factors that modulate ST2 expression on T cells, the effect of IL-33 on helper T cell responses and the role of IL-33 on TREG cell function.

9.
Front Immunol ; 10: 425, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30915078

RESUMO

Control and elimination of blood-stage Plasmodium chabaudi AS infection requires CD4+ Th1 cells that secrete IFN-γ and T follicular help (Tfh) cells together with B cell production of antibody. Foxp3+ regulatory T cells (Tregs) are also crucial to protect the host from immunopathology and severe disease, but these cells can suppress protective immune responses to malaria. The chemokine receptor CXCR3 expressed by activated T cells is important for trafficking of CD4+ Th1 cells to sites of inflammation and infection. Previous studies demonstrated CXCR3 is expressed on CD4+ T cells in the spleen during malaria, but the phenotype was not defined. We identified the phenotype of CD4+ T cells that expressed CXCR3 in C57BL/6 (B6) mice during acute P. chabaudi AS infection by analyzing expression of the transcription factors T-bet and Foxp3. We also investigated if CXCR3 contributes to control of parasite replication and survival. The frequency and number of CD4+CXCR3+ T cells increased dramatically in the spleen of infected B6 mice coincident with increased CD4+IFN-γ+ T cells. CXCR3 was up-regulated on effector CD4+Foxp3- T cells as well as Foxp3+ Tregs. Consistent with our previous observations, CD4+T-bet+Foxp3- T cells increased in B6 mice during acute infection. T-bet+Foxp3+ Tregs also increased significantly and a high frequency of these cells expressed CXCR3 supporting the notion that these cells may be Th1-like Tregs. Despite this, the percentage of CD4+Foxp3+ Tregs from infected B6 mice that migrated in vitro to the CXCR3 ligands CXCL9 and CXCL10 was significantly less than naïve mice. To investigate the in vivo contribution of CXCR3 to control of acute blood-stage malaria, we compared the course and outcome of P. chabaudi AS infection in wild-type (WT) B6 and CXCR3-deficient mice. Parasitemia levels were significantly higher around the time of peak parasitemia in CXCR3-/- compared to WT mice but survival was similar suggesting a role for CXCR3 in controlling parasite replication during acute P. chabaudi AS infection. Together, our findings indicate Th1-like CD4+T-bet+Foxp3+ Tregs that express CXCR3 are induced during acute blood-stage malaria and suggest CXCR3 expression on CD4+ Th1 cells may contribute to their migration to the spleen.

10.
Mucosal Immunol ; 12(3): 746-760, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30872761

RESUMO

CD4+Foxp3+ regulatory T (TREG) cells are critical mediators of peripheral tolerance and modulators of immune responses. Functional adaptation of TREG cells, through acquisition of secondary transcription factors is critical for their effector differentiation towards local inflammatory stimuli including infections. The drivers and consequences of this adaptation of TREG cell function remain largely unknown. Using an unbiased screen, we identified receptors of the IL-1 family controlling the adaptation of TREG cells. Through respiratory infection models, we show that the IL-33 receptor (ST2) and the IL-1 receptor (IL1R1) selectively identify stable and unstable TREG cells at mucosal surfaces, respectively. IL-33, not IL-1, is specifically required for maintaining the suppressive function of TREG cells. In the absence of ST2, TREG cells are prone to lose Foxp3 expression and acquire RORγT and IL1R1, while, in the absence of IL-1R1, they maintain Foxp3 expression and resist the acquisition of a Th17 phenotype. Finally, lack of IL-1 signalling enhances the accumulation of ST2+ TREG over pro-inflammatory TREG cells in a Cryptococcus neoformans infection. These observations show that IL-1 and IL-33 exert opposing functions in controlling the functional adaptation of TREG cells, ultimately dictating the dynamics of adaptive immunity to pathogens.


Assuntos
Criptococose/imunologia , Cryptococcus neoformans/fisiologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Mucosa Respiratória/imunologia , Linfócitos T Reguladores/fisiologia , Animais , Diferenciação Celular , Células Cultivadas , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Tolerância Imunológica , Interleucina-1/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Tipo I de Interleucina-1/genética
11.
J Am Heart Assoc ; 8(1): e009372, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30572753

RESUMO

Background Immune cells are key regulators of the vascular inflammatory response characteristic of hypertension. In hypertensive rodents, regulatory T lymphocytes (Treg, CD 4+ CD 25+) prevented vascular injury, cardiac damage, and endothelial dysfunction of mesenteric arteries. Whether Treg modulate the cerebrovascular damage induced by hypertension is unknown. Methods and Results C57 BL /6 mice were perfused with angiotensin II (Ang II ; 1000 ng/kg per minute) for 14 days and adoptive transfer of 3×105 CD 4+ CD 25+ T cells was performed via 2 intravenous injections. Control mice received a sham surgery and PBS . Treg prevented Ang II -induced neurovascular uncoupling ( P<0.05) and endothelial impairment ( P<0.05), evaluated by laser Doppler flowmetry in the somatosensory cortex. The neuroprotective effect of Treg was abolished when they were isolated from mice deficient in interleukin-10. Administration of interleukin-10 (60 ng/d) to hypertensive mice prevented Ang II -induced neurovascular uncoupling ( P<0.05). Treg adoptive transfer also diminished systemic inflammation induced by Ang II ( P<0.05), examined with a peripheral blood cytokine array. Mice receiving Ang II + Treg exhibited reduced numbers of Iba-1+ cells in the brain cortex ( P<0.05) and hippocampus ( P<0.001) compared with mice infused only with Ang II. Treg prevented the increase in cerebral superoxide radicals. Overall, these effects did not appear to be directly modulated by Treg accumulating in the brain parenchyma, because only a nonsignificant number of Treg were detected in brain. Instead, Treg penetrated peripheral tissues such as the kidney, inguinal lymph nodes, and the spleen. Conclusions Treg prevent impaired cerebrovascular responses in Ang II -induced hypertension. The neuroprotective effects of Treg involve the modulation of inflammation in the brain and periphery.

13.
Proc Natl Acad Sci U S A ; 115(10): E2202-E2209, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-29463754

RESUMO

The translation of mRNAs into proteins serves as a critical regulatory event in gene expression. In the context of cancer, deregulated translation is a hallmark of transformation, promoting the proliferation, survival, and metastatic capabilities of cancer cells. The best-studied factor involved in the translational control of cancer is the eukaryotic translation initiation factor 4E (eIF4E). We and others have shown that eIF4E availability and phosphorylation promote metastasis in mouse models of breast cancer by selectively augmenting the translation of mRNAs involved in invasion and metastasis. However, the impact of translational control in cell types within the tumor microenvironment (TME) is unknown. Here, we demonstrate that regulatory events affecting translation in cells of the TME impact cancer progression. Mice bearing a mutation in the phosphorylation site of eIF4E (S209A) in cells comprising the TME are resistant to the formation of lung metastases in a syngeneic mammary tumor model. This is associated with reduced survival of prometastatic neutrophils due to decreased expression of the antiapoptotic proteins BCL2 and MCL1. Furthermore, we demonstrate that pharmacological inhibition of eIF4E phosphorylation prevents metastatic progression in vivo, supporting the development of phosphorylation inhibitors for clinical use.


Assuntos
Neoplasias da Mama/patologia , Fator de Iniciação 4E em Eucariotos/genética , Fator de Iniciação 4E em Eucariotos/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Neutrófilos/metabolismo , Biossíntese de Proteínas , Microambiente Tumoral , Motivos de Aminoácidos , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Fator de Iniciação 4E em Eucariotos/química , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Metástase Neoplásica , Fosforilação , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
14.
Mediators Inflamm ; 2017: 8390595, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29118468

RESUMO

Inflammatory bowel diseases (IBDs) are diseases characterized by various degrees of inflammation involving the gastrointestinal tract. Ulcerative colitis and Crohn's disease are characterized by a dysregulated immune response leading to structural gut alterations in genetically predisposed individuals. Diverticular disease is characterized by abnormal immune response to normal gut microbiota. IBDs are linked to a lack of physiological tolerance of the mucosal immune system to resident gut microbiota and pathogens. The disruption of immune tolerance involves inflammatory pathways characterized by an unbalance between the anti-inflammatory regulatory T cells and the proinflammatory Th1/Th17 cells. The interaction among T cell subpopulations and their related cytokines, mediators of inflammation, gut microbiota, and the intestinal mucosa constitute the gut "immunological niche." Several evidences have shown that xenobiotics, such as rifaximin, can positively modulate the inflammatory pathways at the site of gut immunological niche, acting as anti-inflammatory agents. Xenobiotics may interfere with components of the immunological niche, leading to activation of anti-inflammatory pathways and inhibition of several mediators of inflammation. In summary, xenobiotics may reduce disease-related gut mucosal alterations and clinical symptoms. Studying the complex interplay between gut immunological niche and xenobiotics will certainly open new horizons in the knowledge and therapy of intestinal pathologies.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Mucosa Intestinal/metabolismo , Intestinos/microbiologia , Microbiota/fisiologia , Xenobióticos/uso terapêutico , Animais , Humanos , Doenças Inflamatórias Intestinais/microbiologia , Intestinos/efeitos dos fármacos
15.
Autoimmunity ; 50(6): 354-362, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28850267

RESUMO

A progressive waning in Foxp3+ regulatory T (Treg) cell function provokes autoimmunity in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D), a cellular defect rescued by prophylactic IL-2 therapy. We showed that most islet-infiltrating Treg cells express inducible T-cell co-stimulator (ICOS) in pre-diabetic NOD mice, and that ICOS+ Treg cells display enhanced fitness and suppressive function in situ. Moreover, T1D progression is associated with decreased expansion and suppressive activity of ICOS+Foxp3+ Treg cells, in islets, an observation consistent with the exacerbated T1D seen in NOD.BDC2.5 mice in which the ICOS pathway is abrogated. Here, we show that a large proportion of islet-resident Treg cells express the KLRG1 marker of terminally differentiation, in contrast to islet-infiltrating ICOS- Treg or Teff cells. We hypothesized that KLRG1 expression designates a subpopulation of ICOS+ Treg cells in islets that progressively loses function, and contributes to the immune dysregulation observed at T1D onset. Indeed, KLRG1-expressing ICOS+ Treg cells are prone to apoptosis, and have an impaired proliferative capacity and suppressive function in vitro and in vivo. T1D protective low-dose IL-2 treatment in vivo could not rescue the loss of KLRG1-expressing Treg cells in situ. While the global pool of Foxp3+ Treg cells displays some degree of functional plasticity in vivo, the KLRG1+ ICOS+ Treg cell subset is particularly susceptible to lose Foxp3 expression and reprogram into Th1- or Th17-like effector T (Teff) cells in the pancreas microenvironment. Overall, KLRG1 expression delineates a subpopulation of dysfunctional Treg cells during T1D progression in autoantigen-specific TCR transgenic NOD mice.


Assuntos
Diabetes Mellitus Experimental/genética , Fatores de Transcrição Forkhead/genética , Ilhotas Pancreáticas/imunologia , Receptores Imunológicos/genética , Linfócitos T Reguladores/imunologia , Animais , Apoptose/genética , Apoptose/imunologia , Autoimunidade/efeitos dos fármacos , Autoimunidade/genética , Proliferação de Células , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Progressão da Doença , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica , Humanos , Hipoglicemiantes/farmacologia , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Interleucina-2/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/patologia , Camundongos , Camundongos Endogâmicos NOD , Receptores Imunológicos/imunologia , Transdução de Sinais , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/patologia
16.
Sci Immunol ; 2(12)2017 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-28783662

RESUMO

CD4+FOXP3+ regulatory T (Treg) cells are critical mediators of immune tolerance, and their deficiency owing to FOXP3 mutations in immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) patients results in severe autoimmunity. Different FOXP3 mutations result in a wide range of disease severity, reflecting the relative importance of the affected residues in the integrity of the FOXP3 protein and its various molecular interactions. We characterized the cellular and molecular impact of the most common IPEX mutation, p.A384T, on patient-derived Treg cells. We found that the p.A384T mutation abrogated the suppressive capacity of Treg cells while preserving FOXP3's ability to repress inflammatory cytokine production. This selective functional impairment is partly due to a specific disruption of FOXP3A384T binding to the histone acetyltransferase Tat-interacting protein 60 (TIP60) (KAT5) and can be corrected using allosteric modifiers that enhance FOXP3-TIP60 interaction. These findings reveal the functional impact of TIP60 in FOXP3-driven Treg biology and provide a potential target for therapeutic manipulation of Treg activity.

17.
J Autoimmun ; 79: 74-83, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28237724

RESUMO

The C1858T single nucleotide polymorphism (SNP) in PTPN22 (protein tyrosine phosphatase nonreceptor 22) leads to the 620 Arg to Trp polymorphism in its encoded human protein LYP. This allelic variant is associated with multiple autoimmune diseases, including type 1 diabetes (T1D), Crohn's disease, rheumatoid arthritis and systemic lupus erythematosus. However, the underlying mechanisms are poorly understood. To study how this polymorphism influences the immune system, we generated a mouse strain with a knock-in of the Trp allele, imitating the human disease-associated variant. We did not find significant difference between the polymorphic and the wild type mice on the proportion of total CD4 T cell, CD8 T cell, NK cell, memory T lymphocyte, macrophage, dendritic cells in both peripheral lymph nodes and spleen. However, macrophages from Trp/Trp mice showed altered morphology and enhanced function, including higher expression of MHCII and B7 molecules and increased phagocytic ability, which further leads to a higher T-cell activation by specific antigen. Our model shows no alteration in immune cell profile by the Trp allele, but brings up macrophages as an important player to consider in explaining the PTPN22 Trp allele effect on autoimmune disease risk.


Assuntos
Substituição de Aminoácidos , Autoimunidade/genética , Códon , Macrófagos/imunologia , Macrófagos/metabolismo , Mutação , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Alelos , Animais , Antígenos B7/genética , Antígenos B7/imunologia , Citocinas/genética , Citocinas/metabolismo , Expressão Gênica , Predisposição Genética para Doença , Genótipo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Macrófagos/citologia , Masculino , Camundongos , Camundongos Transgênicos , Fagocitose/genética , Fagocitose/imunologia , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
18.
J Immunol ; 198(7): 2760-2771, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28219891

RESUMO

IVIg is widely used as an immunomodulatory therapy. We have recently demonstrated that IVIg protects against airway hyperresponsiveness (AHR) and inflammation in mouse models of allergic airways disease (AAD), associated with induction of Foxp3+ regulatory T cells (Treg). Using mice carrying a DTR/EGFP transgene under the control of the Foxp3 promoter (DEREG mice), we demonstrate in this study that IVIg generates a de novo population of peripheral Treg (pTreg) in the absence of endogenous Treg. IVIg-generated pTreg were sufficient for inhibition of OVA-induced AHR in an Ag-driven murine model of AAD. In the absence of endogenous Treg, IVIg failed to confer protection against AHR and airway inflammation. Adoptive transfer of purified IVIg-generated pTreg prior to Ag challenge effectively prevented airway inflammation and AHR in an Ag-specific manner. Microarray gene expression profiling of IVIg-generated pTreg revealed upregulation of genes associated with cell cycle, chromatin, cytoskeleton/motility, immunity, and apoptosis. These data demonstrate the importance of Treg in regulating AAD and show that IVIg-generated pTreg are necessary and sufficient for inhibition of allergen-induced AAD. The ability of IVIg to generate pure populations of highly Ag-specific pTreg represents a new avenue to study pTreg, the cross-talk between humoral and cellular immunity, and regulation of the inflammatory response to Ags.


Assuntos
Imunoglobulinas Intravenosas/imunologia , Hipersensibilidade Respiratória/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Transcriptoma
19.
Front Immunol ; 8: 1844, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29379498

RESUMO

Cellular therapies with CD4+ T regulatory cells (Tregs) hold promise of efficacious treatment for the variety of autoimmune and allergic diseases as well as posttransplant complications. Nevertheless, current manufacturing of Tregs as a cellular medicinal product varies between different laboratories, which in turn hampers precise comparisons of the results between the studies performed. While the number of clinical trials testing Tregs is already substantial, it seems to be crucial to provide some standardized characteristics of Treg products in order to minimize the problem. We have previously developed reporting guidelines called minimum information about tolerogenic antigen-presenting cells, which allows the comparison between different preparations of tolerance-inducing antigen-presenting cells. Having this experience, here we describe another minimum information about Tregs (MITREG). It is important to note that MITREG does not dictate how investigators should generate or characterize Tregs, but it does require investigators to report their Treg data in a consistent and transparent manner. We hope this will, therefore, be a useful tool facilitating standardized reporting on the manufacturing of Tregs, either for research purposes or for clinical application. This way MITREG might also be an important step toward more standardized and reproducible testing of the Tregs preparations in clinical applications.

20.
J Immunol ; 196(2): 533-40, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26747571

RESUMO

The immune system is under strict regulatory control to ensure homeostasis of inflammatory responses, lying dormant when not needed but quick to act when called upon. Small changes in gene expression can lead to drastic changes in lineage commitment, cellular function, and immunity. Conventional assessment of these changes centered on the analysis of mRNA levels through a variety of methodologies, including microarrays. However, mRNA synthesis does not always correlate directly to protein synthesis and downstream functional activity. Work conducted in recent years has begun to shed light on the various posttranscriptional changes that occur in response to a dynamic external environment that a given cell type encounters. We provide a critical review of key posttranscriptional mechanisms (i.e., microRNA) and translational mechanisms of regulation of gene expression in the immune system, with a particular emphasis on these regulatory processes in various CD4(+) T cell subsets.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Regulação da Expressão Gênica/imunologia , MicroRNAs/imunologia , Processamento Pós-Transcricional do RNA/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Humanos
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