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1.
Nat Commun ; 10(1): 4575, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594933

RESUMO

IL-7 is a key factor in T cell immunity and common variants at IL7R, encoding its receptor, are associated with autoimmune disease susceptibility. IL7R mRNA is induced in stimulated monocytes, yet a function for IL7R in monocyte biology remains unexplored. Here we characterize genetic regulation of IL7R at the protein level in healthy individuals, and find that monocyte surface and soluble IL7R (sIL7R) are markedly induced by lipopolysaccharide. In monocytes, both surface IL7R and sIL7R expression strongly associate with allelic carriage of rs6897932, a disease-associated IL7R polymorphism. Monocytes produce more sIL7R than CD4 + T cells, and the amount is additionally correlated with the expression of DDX39A, encoding a splicing factor. Synovial fluid-derived monocytes from patients with spondyloarthritis are enriched for IL7R+ cells with a unique transcriptional profile that overlaps with IL-7-induced gene sets. Our data thus suggest a previously unappreciated function for monocytes in IL-7 biology and IL7R-associated diseases.


Assuntos
Autoimunidade/genética , Subunidade alfa de Receptor de Interleucina-7/genética , Interleucina-7/imunologia , Monócitos/imunologia , Espondilite Anquilosante/genética , Alelos , RNA Helicases DEAD-box/imunologia , RNA Helicases DEAD-box/metabolismo , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Voluntários Saudáveis , Humanos , Interleucina-7/metabolismo , Subunidade alfa de Receptor de Interleucina-7/imunologia , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Lipopolissacarídeos/imunologia , Monócitos/metabolismo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de RNA , Análise de Célula Única , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/patologia , Líquido Sinovial/citologia , Líquido Sinovial/imunologia , Regulação para Cima/imunologia
2.
Mol Immunol ; 114: 323-329, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31442916

RESUMO

Ulcerative colitis (UC) is a chronic relapsing inflammatory disease that occurs in the gastrointestinal tract, characterized by an upregulation in autoantibody production and antimicrobial antibody production. The interaction between follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr) is critical to the induction and regulation of antibody production. In this study, we investigated the characteristics of Tfr cells in UC patients. We gated circulating Tfr cells as CD4+CXCR5+CD25+CD127- T cells, of which approximately 73% on average were Foxp3+. The circulating Tfh (CD4+CXCR5+CD25-) cells from control subjects and UC patients presented a comparable capacity to induce IgM production from naive B cells and to mediate class switching to IgG. Tfr cells significantly reduced Tfh-mediated B cell help in both healthy controls and UC patients in a concentration-dependent manner. However, the suppression capacity of Tfr cells was significantly lower in UC patients than in healthy controls. Subsequently, we found that the frequency of CTLA-4-expressing cells was only slightly lower in UC patients, but the MFI of CTLA-4, however, was markedly lower in UC patients. CTLA-4 blockade nearly abrogated Tfr-mediated suppression of IgM, and significantly reduced Tfr-mediated suppression of IgG. Moreover, CTLA-4 blockade removed the relative advantage of Tfr suppression capacity in healthy controls compared to UC patients. Overall, this study demonstrated that CTLA-4 was required for Tfr-mediated suppression of B cell help, but was expressed at lower levels in UC patients.


Assuntos
Antígeno CTLA-4/imunologia , Colite Ulcerativa/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Formação de Anticorpos/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Fatores de Transcrição Forkhead/imunologia , Humanos , Imunoglobulina M/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-7/imunologia , Masculino , Pessoa de Meia-Idade , Receptores CXCR5/imunologia , Linfócitos T Auxiliares-Indutores/imunologia
3.
PLoS One ; 14(3): e0214379, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30908554

RESUMO

Autoantigen-specific methods to prevent and treat Type 1 Diabetes (T1D) carry high hopes to permanently cure this disease, but have largely failed in clinical trials. One suggested approach to increase the efficacy of islet antigen-specific vaccination is to combine it with a modulator of the T cell response, with the goal of reducing effector differentiation and promoting regulatory T cells (Tregs). Here we asked if addition of antibodies that block the IL-7/IL-7Rα pathway altered the T cell response to islet antigen vaccination and prevented T1D in non-obese diabetic (NOD) mice. Anti-IL-7Rα monoclonal antibodies (mAbs) reduced the numbers of islet antigen-specific T cells generated after vaccination with islet peptides and alum. However, addition of anti-IL-7Rα antibodies to peptide/alum vaccination unexpectedly increased non-specific IFN-γ, IL-2 and IL-10 cytokine production and did not result in improved prevention of T1D onset. In a second approach, we used a conjugate vaccine to deliver islet autoantigens, using Keyhole Limpet Hemocyanin (KLH) as a carrier. Islet antigen-KLH vaccination led to a significant expansion of antigen-specific Tregs and delayed diabetes onset in NOD mice. These outcomes were not further improved by addition of anti-IL-7Rα antibodies. To the contrary, blocking IL-7Rα during vaccination led to non-specific cytokine production and reduced the efficacy of a KLH-conjugated vaccine to prevent T1D. Our study thus revealed that adding anti-IL-7Rα antibodies during autoantigen immunization did not improve the efficacy of such vaccinations to prevent T1D, despite altering some aspects of the T cell response in a potentially advantageous way. Further refinement of this approach will be required to separate the beneficial from the adverse effects of anti-IL-7Rα antibodies to treat autoimmune disease.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Autoantígenos/administração & dosagem , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Subunidade alfa de Receptor de Interleucina-7/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Autoantígenos/imunologia , Proliferação de Células , Diabetes Mellitus Tipo 1/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Imunização , Imunoterapia , Camundongos , Camundongos Endogâmicos NOD , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Vacinação
4.
Front Immunol ; 9: 2562, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30483251

RESUMO

Interleukin-27 (IL-27) plays an important role in regulation of anti-inflammatory responses and autoimmunity; however, the molecular mechanisms of IL-27 in modulation of immune tolerance and autoimmunity have not been fully elucidated. Dendritic cells (DCs) play a central role in regulating immune responses mediated by innate and adaptive immune systems, but regulatory mechanisms of DCs in CD4+ T cell-mediated immune responses have not yet been elucidated. Here we show that IL-27 treated mature DCs induced by LPS inhibit immune tolerance mediated by LPS-stimulated DCs. IL-27 treatment facilitates development of the CD4+ CD127+3G11+ regulatory T cell subset in vitro and in vivo. By contrast, IL-27 treated immature DCs fail to modulate development of the CD4+CD127+3G11+ regulatory T cell sub-population in vitro and in vivo. Our results suggest that IL-27 may break immune tolerance induced by LPS-stimulated mature DCs through modulating development of a specific CD4+ regulatory T cell subset mediated by 3G11 and CD127. Our data reveal a new cellular regulatory mechanism of IL-27 that targets DC-mediated immune responses in autoimmune diseases such as multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE).


Assuntos
Antígenos de Superfície/imunologia , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Subunidade alfa de Receptor de Interleucina-7/imunologia , Interleucinas/imunologia , Lipopolissacarídeos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade/imunologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Tolerância Imunológica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia
5.
J Neuroimmunol ; 324: 81-89, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30248528

RESUMO

Neuromyelitis optica (NMO) is a chronic inflammatory demyelinating autoimmune disease of the central nervous system that most commonly affects the optic nerves and spinal cord. To characterize the immunological pathways involved in NMO, whole blood RNA expression array was performed using Nanostring nCounter technology. Two major clusters of genes were found associated with NMO: T cell-associated genes and the TNF/NF-kB signaling pathway. Analysis of the genes within the first cluster confirmed significantly reduced expression of IL7Ra (CD127) in the peripheral blood of NMO patients vs that in healthy controls. IL7Ra upstream transcription factors and its downstream survival signaling pathway were also markedly reduced. In line with the essential role of IL7Ra in T cell maturation and survival, a significantly lower number of naïve T cells, and reduced T cell survival signaling mediated by increased BID (BH3-interacting domain death agonist) expression and increased apoptosis was observed. Cumulatively, these findings indicate that the IL7Ra signaling pathway may play a role in the autoimmune process in NMO.


Assuntos
Subunidade alfa de Receptor de Interleucina-7/biossíntese , Neuromielite Óptica/metabolismo , Transdução de Sinais/fisiologia , Subpopulações de Linfócitos T/metabolismo , Adulto , Estudos de Coortes , Feminino , Expressão Gênica , Humanos , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/imunologia , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/genética , Neuromielite Óptica/imunologia , Subpopulações de Linfócitos T/imunologia
6.
Viral Immunol ; 31(8): 559-567, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30067145

RESUMO

Direct-acting antivirals (DAAs) not only rapidly inhibited hepatitis C virus (HCV) replication but also modulated innate and adaptive immune response in chronic hepatitis C patients. However, the regulatory activity of DAAs to Toll-like receptor 2 (TLR2) stimulation on CD4+CD25+CD127dim/- regulatory T cells (Tregs) and T helper (Th) 17 cells was not completely understood. In the present study, a total of 23 patients with chronic HCV genotype 1b infection were enrolled, and blood samples were collected at baseline (treatment naive), end of therapy (EOT), and 12 weeks after EOT (SVR12) with daclatasvir plus asunaprevir therapy. TLR2 expression on Tregs and Th17 cells was measured by flow cytometry. Cellular proliferation, cytokine production, and suppressive activity were also tested in purified CD4+CD25+CD127dim/- Tregs in response to the stimulation of Pam3Csk4, an agonist of TLR2. Inhibition of HCV RNA by daclatasvir and asunaprevir did not affect either percentage of Tregs/Th17 cells or TLR2 expression on Tregs/Th17 cells. Pam3Csk4 stimulation also did not influence either cellular proliferation or Tregs/Th17 proportion at each time point. Stimulation with Pam3Csk4 only enhanced the suppressive function and interleukin (IL)-35 production by Tregs purified from baseline, but not those from EOT or SVR12. Similarly, Pam3Csk4 stimulation only elevated Th17 cell frequency of CD4+ T cells from baseline, but not those from EOT or SVR12. Moreover, daclatasvir and asunaprevir therapy did not promote TLR2-induced shift of Tregs toward Th17-like phenotype and function. These data suggested that daclatasvir plus asunaprevir therapy resulted in the decreased responsiveness of Tregs/Th17 cells to TLR2 stimulation in chronic hepatitis C patients, which might provide a novel mechanism underlying DAA-induced immunoregulation.


Assuntos
Antivirais/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Hepatite C Crônica/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Receptor 2 Toll-Like/imunologia , Adolescente , Adulto , Antivirais/administração & dosagem , Feminino , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-7/imunologia , Isoquinolinas/administração & dosagem , Isoquinolinas/uso terapêutico , Cirrose Hepática/diagnóstico , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Tomografia Computadorizada por Raios X , Adulto Jovem
7.
J Immunol Res ; 2018: 1292404, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30003111

RESUMO

CD4+CD25highCD127low/-FoxP3+ regulatory T cells (Tregs) are currently under extensive investigation in childhood acute lymphoblastic leukemia (ALL) and in other human cancers. Usually, Treg cells maintain the immune cell homeostasis. This small subset of T cells has been, in fact, considered to be involved in the pathogenesis of autoimmune diseases and progression of acute and chronic leukemias. However, whether Treg dysregulation in CLL and ALL plays a key role or it rather represents a simple epiphenomenon is still a matter of debate. Treg cells have been proposed as a prognostic indicator of the clinical course of the disease and might also be used for targeted immune therapy. Our study revealed statistically higher percentage of Treg cells in the bone marrow than in peripheral blood in the group of 42 children with acute lymphoblastic leukemia. By analyzing Treg subpopulations, it was shown that only memory Tregs in contact with leukemic antigens showed statistically significant differences. We noticed a low negative correlation between Treg cells in the bone marrow and the percentage of blasts (R = -0.36) as well as a moderate correlation between Treg cells in the bone marrow and Hb level (R = +0.41) in peripheral blood before therapy. The number of peripheral blood blasts on day 8th correlates negatively (R = -0.36) with Tregs. Furthermore, statistical analysis revealed low negative correlation between the number of Tregs in the bone marrow and the minimal residual disease measured on day 15th, the percentage of blasts in the bone marrow and leukocytosis after 15 days of chemotherapy. These results indicate the influence of Tregs on the final therapeutic effect.


Assuntos
Antígenos CD/imunologia , Medula Óssea/imunologia , Fatores de Transcrição Forkhead/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Antígenos CD/sangue , Medula Óssea/patologia , Antígenos CD4/sangue , Antígenos CD4/imunologia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Fatores de Transcrição Forkhead/sangue , Humanos , Imunofenotipagem , Lactente , Subunidade alfa de Receptor de Interleucina-2/sangue , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-7/sangue , Subunidade alfa de Receptor de Interleucina-7/imunologia , Subpopulações de Linfócitos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Linfócitos T Reguladores/patologia
8.
Scand J Immunol ; 87(5): e12661, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29570822

RESUMO

ILC populations elaborate a similar cytokine expression pattern with helper T cell subsets Th1, Th2 and Th17. Recent studies indicate that CD25+ILC2 could alleviate atherosclerosis by altering lipid metabolism, whereas the depletion of CD90-expressing ILCs had no influence on atherosclerosis. Thus, these findings raise the question of whether ILC1 cells react on atherosclerosis. Hence, our group attempted to explore the role of ILC1 cells in atherosclerosis. We found that ILC1 cells have a high Th1-like gene expression of T-bet and IFN-γ, which is distinct from ILC2, ILC3 or conventional NK (cNK) cells. Moreover, atherosclerotic lesions were greatly reduced in ApoE-/-Rag1-/- mice treated with anti-NK1.1 mAbs for depleting ILC1 cells (ILC1+cNK cells), compared to ApoE-/-Rag1-/- mice treated with anti-IL-15R mAbs for depleting cNK cells, and these effects could be fully rescued through the adoptive transfer of ILC1 cells sorted from the spleen of ApoE-/-TLR4+/+ mice into ApoE-/-Rag1-/- mice treated with anti-NK1.1 mAbs. However, the adoptive transfer of ILC1 cells sorted from the spleen of ApoE-/-TLR4-/- mice into ApoE-/-Rag1-/- mice treated with anti-NK1.1 mAbs blocked the progression of atherosclerosis, indicating that the pro-atherosclerotic role of ILC1 cells is dependent on TLR4. Furthermore, oxLDL-induced increase in IFN-γ expression from ApoE-/- ILC1 cells was correlated with the decrease in BACH2 expression. Taken together, ILC1 cells exist in atherosclerosis and aggravate atherosclerosis via increasing pro-inflammatory cytokine expression in a TLR4/BACH2-dependent manner.


Assuntos
Aterosclerose/imunologia , Fatores de Transcrição de Zíper de Leucina Básica/imunologia , Imunidade Inata/imunologia , Células Th1/imunologia , Receptor 4 Toll-Like/imunologia , Animais , Anticorpos Monoclonais/imunologia , Apolipoproteínas E/genética , Fatores de Transcrição de Zíper de Leucina Básica/biossíntese , Células Cultivadas , Proteínas de Homeodomínio/genética , Imunidade Inata/genética , Interferon gama/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Subunidade alfa de Receptor de Interleucina-7/imunologia , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Baço/citologia , Baço/imunologia , Proteínas com Domínio T/genética , Células Th1/transplante
9.
Clin Immunol ; 188: 103-112, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29330114

RESUMO

CD4+ T cells that co-express CD25 and CD127 (CD25+CD127+) make up around 20% of all circulating CD4+ memory T cells in healthy people. The clinical significance of these cells is that in children with type 1 diabetes their relative frequency at diagnosis is significantly and directly correlated with rate of disease progression. The purpose of this study was to further characterize the CD25+CD127hi cells. We show that they are a mix of Th1 and Th2 cells however, they have a significantly higher relative frequency of pre-committed and committed Th2 cells, and secrete significantly higher levels of Th2-type cytokines than CD25- memory T cells. Further, these cells are neither exhausted nor senescent and proliferate to the same extent as CD25- memory cells. Thus, CD25+CD127hi cells are a highly active subset of memory T cells that might play a role in controlling inflammation via anti-inflammatory Th2-type deviation.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-7/imunologia , Subpopulações de Linfócitos T/imunologia , Células Th1/imunologia , Células Th2/imunologia , Linfócitos T CD4-Positivos/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Memória Imunológica/imunologia , Imunofenotipagem , Inflamação/imunologia , Inflamação/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Subpopulações de Linfócitos T/metabolismo , Células Th1/metabolismo , Células Th2/metabolismo
10.
Cytokine ; 102: 26-33, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29275010

RESUMO

Interleukin (IL)-7 is a potent proliferation, activation, and survival cytokine for CD8+ T cells to improve viral and tumor specific CD8+ T cell responses. However, the role of IL-7 in regulation of dysfunctional hepatitis C virus (HCV)-specific CD8+ T cells was not fully elucidated. Thus, a total of 53 patients with chronic hepatitis C and 24 healthy individuals were enrolled in the current study. Serum IL-7 and its receptor α chain CD127 expression was measured. The modulatory function of IL-7 to CD8+ T cells was investigated in both direct and indirect contact co-culture with HCVcc-infected Huh7.5 cells. Both serum IL-7 and CD127 expression on CD8+ T cells was significantly reduced in chronic HCV-infected patients, which was negatively correlated with HCV RNA. Stimulation of IL-7 promoted both cytotoxicity and cytokines (interferon-γ, tumor necrosis factor-α, and IL-2) production of CD8+ T cells from patients with chronic hepatitis C. Moreover, IL-7 increased proliferation of CD8+ T cells, while downregulated a critical repressor of cytokine signaling, suppressor of cytokine signaling 3 (SOCS3). The IL-7-mediated enhancement effects to CD8+ T cells were dependent on IL-6 production. The current data suggested that IL-7 induced both cytolytic and noncytolytic functions of CD8+ T cells probably via repression of SOCS3. IL-7 might be considered as one of the therapeutic candidates for treatment of chronic HCV infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Hepacivirus/fisiologia , Hepatite C Crônica , Hepatócitos , Interleucina-7/farmacologia , Comunicação Celular , Linhagem Celular , Técnicas de Cocultura , Feminino , Hepatite C Crônica/imunologia , Hepatite C Crônica/terapia , Hepatite C Crônica/virologia , Hepatócitos/imunologia , Hepatócitos/virologia , Humanos , Subunidade alfa de Receptor de Interleucina-7/imunologia , Masculino , Proteína 3 Supressora da Sinalização de Citocinas , Replicação Viral/efeitos dos fármacos
11.
Clin Immunol ; 187: 26-32, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28863969

RESUMO

Interleukin-7 is a cytokine essential for T cell homeostasis. IL-7 binds to cellular IL-7 receptors in competition with a soluble form of the receptor (sIL-7Rα). We hypothesized that altered sIL-7Rα levels may cause adverse outcomes in patients undergoing HSCT. In parallel, we investigated the impact of the IL-7Rα SNP rs6897932, which has been associated with release of IL-7R. The sIL-7Rα levels decreased during HSCT (from 114ng/ml before to 48ng/ml at day +14 (P<0.0001)). This pattern was inversely mirrored by IL-7. The IL-7/sIL-7Rα ratio at day +14 was significantly higher in patients developing grades II-IV aGVHD (OR=4.3, P=0.026). Furthermore, donor carriage of the rs6897932 T allele was associated with reduced sIL-7Rα levels, increased risk of grades II-IV aGVHD (OR=2.4, P=0.055) and increased transplant-related mortality (CC=4.5%, CT=21.4% and TT=27.3%, P=0.0037). In conclusion, this study suggests an impact of sIL-7Rα levels and rs6897932 donor genotype on alloreactivity and outcome after HSCT.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Subunidade alfa de Receptor de Interleucina-7/imunologia , Interleucina-7/imunologia , Leucemia/terapia , Linfoma não Hodgkin/terapia , Doenças Mieloproliferativas-Mielodisplásicas/terapia , Doença Aguda , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mortalidade , Polimorfismo de Nucleotídeo Único , Linfócitos T/imunologia , Trombocitemia Essencial/terapia , Transplante Homólogo , Adulto Jovem
12.
Cytometry B Clin Cytom ; 94(2): 264-269, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-27479496

RESUMO

BACKGROUND: CD4+ FoxP3+ regulatory T cells (Tregs) are the potent suppressors of activation and proliferation of conventional T cells. Tregs subdivided by their expression of FoxP3 and CD45RA identify clinically important functional subsets. METHODS: We analyzed Treg subpopulations in hematopoietic stem cell harvests (SCH) from 22 allogeneic (matched unrelated and sibling) donors with flow cytometry by their expression of CD45RA, CD127, CD25, and FoxP3 marker combinations. RESULTS: A high fraction of "activated Tregs", defined as CD4+ FoxP3hi CD45RAlo (aTreg) cells relative to all CD4+ T-cells, in the SCH correlated with no subsequent development of acute graft-versus-host disease (aGVHD) in the corresponding transplant recipients (aTreg 1.29%, range 0.96-1.64%, vs. 0.23%, range 0.14-0.56%, with subsequent aGvHD; P = 0.0015). The "non-Treg" cells, defined by CD4+ FoxP3med/lo CD45RAlo , and resting Treg (rTreg) cells, defined by CD4+ FoxP3med CD45RAhi , did not correlate with aGvHD development. We also showed that phenotypic aTregs could be induced in vitro from nonTregs under homeostatic proliferation conditions and that this ability correlated with the CD127 and CD25 expression patterns. CONCLUSIONS: We identified a subset of T CD4+ FoxP3+ cells, i.e., aTregs that were correlated to aGvHD development, and demonstrated plasticity of the nonTreg population to provide phenotypic aTregs. This could have both a predictive clinical relevance in inflammatory conditions as well as support a rationale for development of cell targeted therapy. © 2016 International Clinical Cytometry Society.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Células-Tronco Hematopoéticas/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/imunologia , Feminino , Citometria de Fluxo/métodos , Fatores de Transcrição Forkhead/imunologia , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-7/imunologia , Antígenos Comuns de Leucócito/imunologia , Masculino , Pessoa de Meia-Idade , Transplantados , Transplante Homólogo/métodos , Adulto Jovem
13.
Clin Immunol ; 187: 15-25, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28941836

RESUMO

Genetic variants within some cytokine receptor genes have been associated with MS susceptibility, including IL7RA and IL2RA. As these genes are expressed by cells targeted by immune-modulatory drugs, we explored the potential role of their gene products as biomarkers in monitoring MS treatment. We assessed the impact of natalizumab followed by fingolimod on the intra-individual changes of plasma protein levels of sIL-7Rα, sIL-2Rα and also sIL-6R and sgp130 in MS patients. During natalizumab treatment we observed a decline in sgp130 and sIL-7Rα levels, while subsequent fingolimod treatment lead to increased sgp130 and sIL-7Rα and decreased sIL-2Rα levels. In addition, during fingolimod treatment sIL-7Rα levels were increasing significantly more in patients homozygous for the MS risk genotype of rs6897932. We also observed an effect of the MS associated rs71624119 on sgp130 levels. These results may elucidate the pharmacodynamics of treatments and help identify biomarkers for MS outcomes.


Assuntos
Cloridrato de Fingolimode/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Natalizumab/uso terapêutico , Adolescente , Adulto , Receptor gp130 de Citocina/genética , Receptor gp130 de Citocina/imunologia , Feminino , Variação Genética , Humanos , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/imunologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Testes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Adulto Jovem
14.
COPD ; 14(6): 618-625, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29166179

RESUMO

Human regulatory T cells (Tregs) have been reported to be not significantly different in the peripheral blood of patients with chronic obstructive pulmonary disease (COPD) and healthy controls. Recent research has identified some new markers for Tregs and indicated that Tregs are composed of distinct subpopulations. The aim of the study was to describe the changing patterns of circulating Treg subpopulations in patients with acute exacerbation of COPD (AECOPD) and healthy controls, and to explore their potential roles in AECOPD pathogenesis. Blood samples were obtained from 30 never-smokers with normal lung function and 30 patients with COPD before and after they had an exacerbation. The proportions of Treg subpopulations were evaluated using flow cytometry. In the peripheral blood, decreased proportions of CD4+CD25+CD127low Tregs, CD4+CD25+CD45RA+ Tregs, and CD4+CD25+CD62L+ Tregs and an increased proportion of CD4+CD25+CD45RO+ Tregs were found in patients with stable COPD compared with non-smokers with normal lung function. The patients showed further changes in Treg subpopulations when they had an AECOPD, with an overall decrease in a suppressive subset, indicating that the immune negative regulatory population of Tregs did not play an effective role. Immune homeostasis favored inflammation, and a negative correlation between the circulating tumor necrosis factor-alpha and the proportions of CD4+CD25+CD62L+ cells (r = -0.698, p < 0.05) in patients with AECOPD was found. The imbalance between the suppressive subsets and the proinflammatory subset of Tregs and the decline of Treg subpopulations with immunosuppressive activity may play important roles in AECOPD progression.


Assuntos
Doença Pulmonar Obstrutiva Crônica/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Idoso , Antígenos CD4/imunologia , Estudos de Casos e Controles , Progressão da Doença , Feminino , Citometria de Fluxo , Volume Expiratório Forçado , Humanos , Inflamação/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-7/imunologia , Selectina L/imunologia , Antígenos Comuns de Leucócito/imunologia , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fumar/imunologia , Capacidade Vital
15.
Proc Natl Acad Sci U S A ; 114(42): E8865-E8874, 2017 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-28973925

RESUMO

The factors and steps controlling postinfection CD8+ T cell terminal effector versus memory differentiation are incompletely understood. Whereas we found that naive TCF7 (alias "Tcf-1") expression is FOXO1 independent, early postinfection we report bimodal, FOXO1-dependent expression of the memory-essential transcription factor TCF7 in pathogen-specific CD8+ T cells. We determined the early postinfection TCF7high population is marked by low TIM3 expression and bears memory signature hallmarks before the appearance of established memory precursor marker CD127 (IL-7R). These cells exhibit diminished TBET, GZMB, mTOR signaling, and cell cycle progression. Day 5 postinfection, TCF7high cells express higher memory-associated BCL2 and EOMES, as well as increased accumulation potential and capacity to differentiate into memory phenotype cells. TCF7 retroviral transduction opposes GZMB expression and the formation of KLRG1pos phenotype cells, demonstrating an active role for TCF7 in extinguishing the effector program and forestalling terminal differentiation. Past the peak of the cellular immune response, we report a gradient of FOXO1 and TCF7 expression, which functions to oppose TBET and orchestrate a continuum of effector-to-memory phenotypes.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Proteína Forkhead Box O1/metabolismo , Memória Imunológica/fisiologia , Animais , Infecções por Arenaviridae/imunologia , Infecções por Arenaviridae/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Diferenciação Celular , Proteína Forkhead Box O1/genética , Granzimas/genética , Granzimas/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/imunologia , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Subunidade alfa de Receptor de Interleucina-7/imunologia , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Receptores Imunológicos/metabolismo
16.
Cell Immunol ; 319: 3-9, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28844471

RESUMO

The immunological mechanism(s) of action whereby teplizumab preserves C-peptide levels in the progression of patients with recent onset type 1 diabetes (T1D) is still not well understood. In the present study, we evaluated the kinetics of T cell modulation in peripheral blood following two 14-day courses of teplizumab therapy one year apart in recent onset T1D participants in the AbATE clinical trial. Transient rises in PD-1+Foxp3+ Treg and potentially anergic (CD57-KLRG1-PD-1+) cells in the circulating CD4 T cell compartment were paralleled by more profound increases in circulating CD8 T cells with traits of exhaustion (CD57-KLRG1+PD-1+, TIGIT+KLRG1+, and persistent down-modulation of CD127). The observed phenotypic changes across cell types were associated with favorable response to treatment in the subgroup of study participants that did not develop anti-drug antibodies after the first course of therapy. These findings provide new insights on the duration and complexity of T cell modulation with teplizumab therapy in recent onset T1D, and in addition, suggest that coordinated immune mechanisms of tolerance that favor CD4 Treg function and restrain CD4 non-Treg and CD8 T cell activation may contribute to treatment success.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Tolerância Imunológica/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Adolescente , Adulto , Peptídeo C/agonistas , Peptídeo C/genética , Peptídeo C/imunologia , Complexo CD3/genética , Complexo CD3/imunologia , Antígenos CD57/genética , Antígenos CD57/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Criança , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Expressão Gênica , Humanos , Imunomodulação , Imunoterapia/métodos , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/imunologia , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Masculino , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Transativadores/genética , Transativadores/imunologia
17.
Pancreas ; 46(8): 1003-1010, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28787335

RESUMO

OBJECTIVE: Early detection of severe forms with unfavorable outcome is the cornerstone that could provide reduction of morbidity and mortality in acute pancreatitis (AP). METHODS: The percentage of circulating CD4CD25CD127 regulatory T-cells (Tregs) was determined at admission, on the 48th hour, and on the fifth day in 72 patients with AP. We divided patients in 2 groups-Sev1, which includes 19 patients (26.4%) with moderate AP and 39 patients (54.2%) with mild disease, and Sev2, which includes 14 patients (19.4%) with severe AP. Seven patients (9.7%) developed septic complications. The mortality in our group was 9.7%. RESULTS: The patients in Sev2 had higher percentage of Tregs at admission and on the fifth day compared with patients in Sev1 (P = 0.007 and P = 0.033, respectively). There was no significant difference in percentage of Tregs at admission, on the 48th hour, and on the fifth day in patients who developed and did not develop infected necrosis (P = 0.50, P = 0.72, and P = 0.92, respectively). Patients with poor outcome had elevated percentage of Tregs on the fifth day (P = 0.045). CONCLUSIONS: The percentage of circulating Tregs may be implicated in the development of early immune suppression in AP. Elevated percentage of circulating Tregs at admission in AP is an independent prognostic biomarker for severe disease.


Assuntos
Biomarcadores/sangue , Pancreatite/sangue , Pancreatite/imunologia , Linfócitos T Reguladores/imunologia , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-7/imunologia , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pancreatite/mortalidade , Prognóstico , Índice de Gravidade de Doença , Taxa de Sobrevida , Linfócitos T Reguladores/metabolismo , Fatores de Tempo , Adulto Jovem
18.
Mol Med Rep ; 16(3): 2893-2898, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28677759

RESUMO

Previous studies have indicated that regulatory T cells serve essential roles in maintaining intestinal homeostasis, however, the role of different Treg subsets in modulating inflammatory bowel disease has still not been addressed clearly. In the present study, the authors measured the percentage of Foxp3+ IL­10+ TGF­ß+ natural Tregs, Foxp3­ IL­10+ TGF­ß­ induced Tregs, CD127­ induced Tregs and CD8+ Tregs at different time points in DSS­induced experimental colitis model in murine lamina propria lymphocytes, mesenteric lymph node and peripheral blood. In addition, the authors compared the frequency of four Treg subsets in patients diagnosed of ulcerative colitis at different stages with enrolled healthy controls. The percentage of Foxp3+ IL­10+ TGF­ß+ natural Tregs decreased in acute stage of both human and mice was observed, but proliferated significantly during remittent stage. Foxp3­ IL­10+ TGF­ß­ inducible (i) Treg and CD127­ iTreg was observed as being significantly decreased percentage in LPL at 4 and 7 days, the frequency of Foxp3­ IL­10+ TGF­ß­ iTreg cells became decreased and CD127­ iTreg only slightly increased at the chronic stage following DSS induction. However, the proportion of both Foxp3­ IL­10+ TGF­ß­ iTreg and CD127­ iTreg was nearly unchanged in human IBD. Although intestinal inflammation decreased the percentage of CD8+ Tregs, it remained lower in the remittent stage of human IBD. Only enhanced proliferation of lamina propria lymphocytes­derived CD8+ Treg was reported at 7 days in dextran sodium sulfate­induced murine colitis. The results demonstrated that Foxp3+ IL­10+ TGF­ß+ natural Tregs may serve an essential role in exhibiting suppressive and protecting from immune­related mucosal injury during chronic stage in inflammatory bowel disease.


Assuntos
Colite/imunologia , Doenças Inflamatórias Intestinais/imunologia , Linfócitos T Reguladores/imunologia , Animais , Colite/induzido quimicamente , Colite/patologia , Sulfato de Dextrana , Fatores de Transcrição Forkhead/análise , Fatores de Transcrição Forkhead/imunologia , Humanos , Doenças Inflamatórias Intestinais/patologia , Interleucina-10/análise , Interleucina-10/imunologia , Subunidade alfa de Receptor de Interleucina-7/análise , Subunidade alfa de Receptor de Interleucina-7/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/patologia , Fator de Crescimento Transformador beta/análise , Fator de Crescimento Transformador beta/imunologia
19.
Sci Rep ; 7(1): 3501, 2017 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-28615725

RESUMO

For many years, human peripheral blood natural killer (NK) cells have been divided into functionally distinct CD3- CD56bright CD16- and CD3- CD56dim CD16+ subsets. Recently, several groups of innate lymphoid cells (ILC), distinct from NK cells in development and function, have been defined in mouse. A signature of genes present in mouse ILC except NK cells, defined by Immunological Genome Project studies, is significantly over-represented in human CD56bright cells, by gene set enrichment analysis. Conversely, the signature genes of mouse NK cells are enriched in human CD56dim cells. Correlations are based upon large differences in expression of a few key genes. CD56bright cells show preferential expression of ILC-associated IL7R (CD127), TNFSF10 (TRAIL), KIT (CD117), IL2RA (CD25), CD27, CXCR3, DPP4 (CD26), GPR183, and MHC class II transcripts and proteins. This could indicate an ontological relationship between human CD56bright cells and mouse CD127+ ILC, or conserved networks of transcriptional regulation. In line with the latter hypothesis, among transcription factors known to impact ILC or NK cell development, GATA3, TCF7 (TCF-1), AHR, SOX4, RUNX2, and ZEB1 transcript levels are higher in CD56bright cells, while IKZF3 (AIOLOS), TBX21 (T-bet), NFIL3 (E4BP4), ZEB2, PRDM1 (BLIMP1), and RORA mRNA levels are higher in CD56dim cells.


Assuntos
Complexo CD3/genética , Antígeno CD56/genética , Subunidade alfa de Receptor de Interleucina-7/genética , Células Matadoras Naturais/metabolismo , Transcriptoma , Animais , Complexo CD3/sangue , Complexo CD3/imunologia , Antígeno CD56/sangue , Antígeno CD56/imunologia , Perfilação da Expressão Gênica , Humanos , Subunidade alfa de Receptor de Interleucina-7/sangue , Subunidade alfa de Receptor de Interleucina-7/imunologia , Células Matadoras Naturais/imunologia , Camundongos , Especificidade da Espécie
20.
Arthritis Rheumatol ; 69(10): 2038-2051, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28622456

RESUMO

OBJECTIVE: Follicular helper T (Tfh) cells play a critical role in germinal center formation and B cell activation, both of which are hallmarks of primary Sjögren's syndrome (SS). CCR9-expressing T helper cells have "Tfh-like" characteristics and their numbers are increased at mucosa-associated sites in several inflammatory conditions. Because the characteristics of these cells are unique and evaluation has been limited, this study was undertaken to investigate the local and systemic CCL25/CCR9 axis in patients with primary SS. METHODS: Levels of CCL25 protein and messenger RNA (mRNA) and CCR9+ T helper cells were evaluated in the labial salivary glands (LSGs) of patients with primary SS and patients with sicca syndrome without a diagnosis of primary SS (non-SS sicca controls). CCL25 levels were assessed for correlation with parameters of inflammation and clinical features. Circulating CCR9+ and CXCR5+ T helper cells were compared on the basis of phenotypic and functional properties. RESULTS: CCL25 protein and mRNA levels were elevated in the LSGs of patients with primary SS as compared to non-SS sicca controls. Increased levels of CCL25 were associated with B cell hyperactivity, autoimmunity, and levels of interleukin-21 (IL-21) and soluble IL-7 receptor α-chain (IL-7Rα). Furthermore, the frequency of CCR9-expressing cells in the LSGs was increased and levels of circulating CCR9+ T helper cells expressing programmed death 1 and inducible T cell costimulator were elevated in patients with primary SS. CCR9+ T helper cells displayed higher expression of IL-7Rα and secreted higher levels of interferon-γ, IL-17, IL-4, and IL-21 as compared to CXCR5+ T helper cells, ex vivo and upon triggering with antigen or IL-7. Both CCR9+ and CXCR5+ T helper cells induced IgG production by B cells more potently than that induced in the cultures with CCR9-CXCR5- T helper cells. CONCLUSION: Enhanced expression of CCL25 in LSGs of patients with primary SS can facilitate attraction of CCR9+ T helper cells, and these cells secrete high levels of proinflammatory cytokines when triggered with antigen or IL-7. The observed associations with B cell hyperactivity, autoimmunity, and markers of lymphoid neogenesis indicate that the CCL25/CCR9 axis plays a significant role in the immunopathology of primary SS, suggesting that this axis could represent a novel therapeutic target for the disease.


Assuntos
Quimiocinas CC/imunologia , Glândulas Salivares Menores/imunologia , Síndrome de Sjogren/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Idoso , Autoimunidade/imunologia , Linfócitos B/imunologia , Estudos de Casos e Controles , Quimiocinas CC/genética , Feminino , Humanos , Imunoglobulina G/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Interferon gama/imunologia , Interleucina-17/imunologia , Interleucina-4/imunologia , Subunidade alfa de Receptor de Interleucina-7/imunologia , Interleucinas/imunologia , Lábio , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/imunologia , RNA Mensageiro , Receptores CCR/imunologia , Receptores CXCR5/imunologia
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