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1.
Immunity ; 51(6): 1119-1135.e5, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31757672

RESUMO

T cells play important multifaceted roles during dengue infection, and understanding their responses is important for defining correlates of protective immunity and identifying effective vaccine antigens. Using mass cytometry and a highly multiplexed peptide-HLA (human leukocyte antigen) tetramer staining strategy, we probed T cells from dengue patients-a total of 430 dengue and control candidate epitopes-together with key markers of activation, trafficking, and differentiation. During acute disease, dengue-specific CD8+ T cells expressed a distinct profile of activation and trafficking receptors that distinguished them from non-dengue-specific T cells. During convalescence, dengue-specific T cells differentiated into two major cell fates, CD57+ CD127--resembling terminally differentiated senescent memory cells and CD127+ CD57--resembling proliferation-capable memory cells. Validation in an independent cohort showed that these subsets remained at elevated frequencies up to one year after infection. These analyses aid our understanding of the generation of T cell memory in dengue infection or vaccination.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Vírus da Dengue/imunologia , Dengue/imunologia , Antígenos HLA/imunologia , Adulto , Linfócitos B/imunologia , Antígenos CD57/metabolismo , Diferenciação Celular/imunologia , Proliferação de Células/fisiologia , Epitopos de Linfócito T/imunologia , Feminino , Antígenos HLA/classificação , Humanos , Memória Imunológica/imunologia , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade
2.
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
3.
Acta Derm Venereol ; 99(6): 579-586, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30809683

RESUMO

Prurigo nodularis is a highly pruritic and hyperplastic chronic dermatosis with unknown pathogenesis. Many pruritogenic mediators, including nerve growth factor, interleukin (IL)-31, thymic stromal lymphopoietin, and endothelin-1, are implicated in chronic itch and inflammation. This study investigated the mRNA levels and immunoreactivity of the nerve growth factor, IL-31, thymic stromal lymphopoietin, and endothelin axes in both lesional and perilesional skin in prurigo nodularis by using quantitative real-time PCR and immunohistochemistry studies. The nerve growth factor high-affinity receptor tyrosine kinase receptor A was upregulated while the low affinity receptor p75 neurotrophin receptor was downregulated in prurigo nodularis lesions. Downregulated expression of IL-31/IL-31 receptor A and endothelin-3/endothelin receptor B and upregulation of thymic stromal lymphopoietin receptor were found in prurigo nodularis lesions. Aberrant expression of nerve growth factor, IL-31, thymic stromal lymphopoietin and endothelin axes was found in prurigo nodularis lesions, especially in the epidermis, indicating the importance of keratinocytes in prurigo nodularis pathogenesis.


Assuntos
Epiderme/metabolismo , Queratinócitos/metabolismo , Prurigo/genética , Prurigo/metabolismo , Adulto , Citocinas/genética , Citocinas/metabolismo , Regulação para Baixo , Endotelina-3/genética , Endotelina-3/metabolismo , Feminino , Expressão Gênica , Humanos , Hipersensibilidade/complicações , Hipersensibilidade/genética , Hipersensibilidade/metabolismo , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Prurigo/complicações , RNA Mensageiro/metabolismo , Receptor de Endotelina B/genética , Receptor de Endotelina B/metabolismo , Receptor trkA/genética , Receptor trkA/metabolismo , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/metabolismo , Regulação para Cima
5.
Gastroenterology ; 156(6): 1805-1819.e9, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30664876

RESUMO

BACKGROUND & AIM: Hepatitis D virus (HDV) superinfection of patients with chronic HBV infection results in rapid progression to liver cirrhosis. Little is known about HDV-specific T cells and how they contribute to the antiviral immune response and liver disease pathogenesis. METHODS: We isolated peripheral blood mononuclear cells from 28 patients with chronic HDV and HBV infection, identified HDV-specific CD8+ T-cell epitopes, and characterized HDV-specific CD8+ T cells. We associated these with HDV sequence variations and clinical features of patients. RESULTS: We identified 6 CD8+ T-cell epitopes; several were restricted by multiple HLA class I alleles. HDV-specific CD8+ T cells were as frequent as HBV-specific CD8+ T cells but were less frequent than T cells with specificity for cytomegalovirus, Epstein-Barr virus, or influenza virus. The ex vivo frequency of activated HDV-specific CD8+ T cells correlated with transaminase activity. CD8+ T-cell production of interferon gamma after stimulation with HDV peptides correlated inversely with HDV titer. HDV-specific CD8+ T cells did not express the terminal differentiation marker CD57, and fewer HDV-specific than Epstein-Barr virus-specific CD8+ T cells were 2B4+CD160+PD1+, a characteristic of exhausted cells. Approximately half of the HDV-specific CD8+ T cells had a memory-like PD1+CD127+TCF1hiT-betlow phenotype, which associated with HDV sequence variants with reduced HLA binding and reduced T-cell activation. CONCLUSIONS: CD8+ T cells isolated from patients with chronic HDV and HBV infection recognize HDV epitopes presented by multiple HLA molecules. The subset of activated HDV-specific CD8+ T cells targets conserved epitopes and likely contributes to disease progression. The subset of memory-like HDV-specific CD8+ T cells is functional but unable to clear HDV because of the presence of escape variants. ClinicalTrials.gov, Numbers: NCT02511431, NCT00023322, NCT01495585, and NCT00001971. GenBank accession, Number: MK333199-333226.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T , Hepatite B Crônica/imunologia , Hepatite D Crônica/imunologia , Vírus Delta da Hepatite/imunologia , Adulto , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Citomegalovirus/imunologia , Feminino , Antígenos HLA-A/metabolismo , Antígenos HLA-B/metabolismo , Vírus da Hepatite B/imunologia , Hepatite D Crônica/sangue , Vírus Delta da Hepatite/genética , Antígenos da Hepatite delta/imunologia , Herpesvirus Humano 4/imunologia , Humanos , Memória Imunológica/imunologia , Vigilância Imunológica/imunologia , Vírus da Influenza A/imunologia , Interferon gama/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Masculino , Pessoa de Meia-Idade , Peptídeos/imunologia , Fenótipo , Receptor de Morte Celular Programada 1/metabolismo , Adulto Jovem
6.
Scand J Immunol ; 89(2): e12736, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30485902

RESUMO

Epithelial ovarian cancer (EOC) is one of the major malignant cancers with high rates of early metastasis in which regulatory T cells (Tregs) play an important role. Tregs suppress immune responses and promote the development of tumours in patients with EOC. However, the underlying mechanisms remain unclear. In this study, we found higher levels of CD4+ CD25high CD127low Tregs in patients with EOC than in patients with benign ovarian tumours and healthy donors. The immune inhibitory effect of Tregs functions by maintaining high levels of immunosuppressive cytokines in EOC. The high levels of Tregs and related cytokines (TGF-ß1 or IL-10) were associated with lymphatic metastasis and FIGO stages of patients with EOC. Expression of matrix metalloproteinase (MMP)-2 and tissue inhibitors of metalloproteinase (TIMP)-2 in EOC cell lines were significantly regulated in the coculture experiment with CD4+ CD25high CD127low Tregs sorted from EOC patients. Levels of MMP-2 and TIMP-2 conversely changed after blocking IL-10R and TGF-ß1R in EOC cells. The invasion ability of EOC cells was also significantly downregulated in this process. The metastasis of EOC cells was correlated with the levels of TGF-ß1 or IL-10. These findings suggested that immunosuppressive cytokines secreted by CD4+ Tregs could be a novel target for inhibiting EOC progression.


Assuntos
Anticorpos Bloqueadores/uso terapêutico , Carcinoma Epitelial do Ovário/terapia , Imunoterapia/métodos , Interleucina-10/metabolismo , Neoplasias Ovarianas/terapia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta1/metabolismo , Antígenos CD4/metabolismo , Carcinogênese , Carcinoma Epitelial do Ovário/imunologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Feminino , Humanos , Imunização , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Metástase Linfática , Ativação Linfocitária , Neoplasias Ovarianas/imunologia , Receptores de Interleucina-10/imunologia , Evasão Tumoral
7.
Immunol Invest ; 48(1): 64-78, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30325682

RESUMO

PURPOSE: Impairment in number and functions of regulatory T cells (Treg) has been found to be associated with many autoimmune diseases including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This study was conducted to identify and compare Treg by flow cytometry using two different staining approaches. METHODS: Treg were identified by using CD4+CD25+high and CD4+CD25+CD127dim staining approaches in SLE and RA patients and healthy controls. Association of both identified Treg levels with various serum markers and clinical presentation was also examined. RESULTS: Blood CD4+CD25+CD127dim cells levels were 11.4+3.57 %, 9.76+2.37 % and 6.95+1.16 %; while CD4+CD25+high cells were 1.46+1.09 %, 0.95+0.59 % and 1.87+1.14 % in SLE patients, RA patients and healthy controls respectively. Number of CD4+CD25+CD127dim cells was higher than CD4+CD25+high cells in blood samples of all three study groups. Levels of CD4+CD25+CD127dim cells were significantly higher in SLE and RA patients, compared to healthy controls, but this difference was not observed for CD4+CD25+high Treg. CD4+CD25+high levels showed significant correlation with serum C4, IFN-γ and IL-10 levels in healthy subjects and with C4 levels and fever in SLE patients. CD4+CD25+CD127dim levels showed significant association with alopecia and oral ulcers in SLE patients only, but no correlation with measured serum markers. CONCLUSION: Results suggest that both staining approaches detect Treg differently and also that Treg play different role in pathogenesis of SLE and RA.


Assuntos
Alopecia/imunologia , Artrite Reumatoide/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Úlceras Orais/imunologia , Linfócitos T Reguladores/imunologia , Biomarcadores/sangue , Separação Celular , Complemento C4/metabolismo , Citometria de Fluxo , Humanos , Interferon gama/sangue , Interleucina-10/sangue , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo
8.
Mol Carcinog ; 58(3): 358-365, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30362635

RESUMO

Interleukin-7(IL-7) can regulate proliferation and apoptosis of cell and also regulate tumor lymphangiogenesis, but whether it regulating autophagy of tumor cells is not well known. We study the relationship between IL-7 and some autophagy-related markers, Beclin 1 and mammalian target of rapamycin (mTOR) and the mechanism of IL-7 in regulating autophagy of human lung cancer cells. We detected expression of Beclin 1 and mTOR in lung cancer cells and their impact on the prognosis of lung cancer patients. Using Western blot and Reverse Transcription PCR, we found that IL-7 activates PI3 K/Akt/mTOR signaling pathway by downregulated the expression of Beclin 1 in lung cancer cell lines. In addition, the expressions of Beclin 1 and mTOR were well correlated with clinical stages and survival of human non-small cell lung cancer (NSCLC) patients. IL-7R, mTOR, and tumor stage were the independent prognosticators in lung cancer. Taken together, our results provided evidence that IL-7 activates PI3 K/Akt/mTOR signaling pathway via Beclin 1 to regulate autophagy in lung cancer cells.


Assuntos
Proteína Beclina-1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Neoplasias Pulmonares/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Adenocarcinoma/terapia , Apoptose , Proteína Beclina-1/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundário , Carcinoma de Células Escamosas/terapia , Proliferação de Células , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa de Receptor de Interleucina-7/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Fosfatidilinositol 3-Quinases/genética , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Taxa de Sobrevida , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais Cultivadas
9.
J Immunol ; 201(11): 3401-3410, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30373848

RESUMO

Sepsis, one of the leading causes of death in intensive care units, is caused by a dysregulated host response to infection that leads to life-threatening organ dysfunction. The proinflammatory and anti-inflammatory responses activated by the infecting microorganism become systemic, and the sustained anti-inflammatory response induces a state of immunosuppression that is characterized by decreased expression of HLA-DR on monocytes, T cell apoptosis, and reduced production of TNF-α by monocytes and macrophages in response to TLR ligands. Innate lymphoid cells (ILCs) are lymphocytes that lack Ag-specific receptors and lineage-specific markers; they express HLA-DR and are activated by cytokines and by direct recognition of microbial molecules. In this study, we evaluated if ILCs are affected by the anti-inflammatory response during sepsis. We found that the number of peripheral blood ILCs was decreased in septic patients compared with healthy volunteers; this decrease was caused by a reduction in ILC1 and ILC3 and is associated with apoptosis, because ILCs from septic patients expressed active caspase 3. ILCs from septic patients had decreased HLA-DR expression but increased expression of the activating receptors NKp46 and NKp44; they also showed a sustained expression of CD127 (IL-7R α-chain) and retained their capacity to produce TNF-α in response to TLR ligands. These results indicate that during sepsis, ILCs have decreased HLA-DR expression and die via apoptosis, similar to monocytes and T cells, respectively. However, other effector functions of ILCs (activation through NKp46 and NKp44, TNF-α production) may remain unaffected by the immunosuppressive environment prevailing in septic patients.


Assuntos
Subunidade alfa de Receptor de Interleucina-7/metabolismo , Linfócitos/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Receptor 2 Desencadeador da Citotoxicidade Natural/metabolismo , Sepse/imunologia , Adulto , Apoptose , Regulação para Baixo , Feminino , Antígenos HLA-DR/metabolismo , Humanos , Imunidade Inata , Masculino , Pessoa de Meia-Idade , Receptores Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
10.
J Immunol Res ; 2018: 7103219, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30255107

RESUMO

Background: Accumulating evidence indicates that a deficiency in or dysfunction of regulatory T cells (Tregs) is involved in the pathogenesis of systemic lupus erythematosus (SLE). As different markers have been used to identify Tregs, recent studies on the proportions of Tregs in SLE patients have generated controversial results. To clarify the status of Tregs in such patients, we determined the proportions of Tregs present during development of the disease, with special consideration of controversial cellular markers. Methods: We identified studies reporting the proportions of Tregs in SLE patients by searching relevant databases through March 2018. Using the PRISMA guidelines, we performed a random effects meta-analysis of the frequencies of Tregs defined in different ways. Inconsistency was evaluated using the I-squared index (I2), and publication bias was assessed by examining funnel plot asymmetry using the Begger and Egger tests. Results: Forty-four studies involving 2779 participants were included in the meta-analysis. No significant difference in the proportions of Tregs was evident between 1772 patients and 1007 controls [-0.191, (-0.552, 0.362), p = 0.613, I2 = 95.7%]. We next conducted subanalyses based on individual definitions of Tregs. When the Treg definition included "FOXP3-positive" cells, the proportions did not differ between SLE patients and controls [-0.042, (-0.548, 0.632), p = 0.889, I2 = 96.6%]; this was the case when Tregs were defined as either "CD25low/-FOXP3+" or "CD25high/+FOXP3+" cells. SLE patients had lower proportions of Tregs that were "single CD25-positive" [-1.428, (-1.982, -0.873), p < 0.001, I2 = 93.4%] and "CD127-negative" [-1.093, (-2.002, -0.183), p = 0.018, I2 = 92.6%] compared to controls. Tregs defined as "CD25bright," "CD25bright/highCD127low/-," and "CD25highCD127low/-FOXP3+" did not differ in proportion between SLE patients and controls. Conclusions: The Treg proportions varied by the cellular identification method used. The proportions of Tregs that were accurately identified and functionally validated fell among patients with SLE. Stricter definitions of Tregs are necessary when evaluating the status of such patients.


Assuntos
Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T Reguladores/imunologia , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Contagem de Linfócitos
12.
Int J Mol Sci ; 19(9)2018 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-30149646

RESUMO

Interleukin-7 (IL-7) is essential for lymphocyte development. To identify the functional subdomains in the cytoplasmic tail of the IL-7 receptor (IL-7R) α chain, here, we constructed a series of IL-7Rα deletion mutants. We found that IL-7Rα-deficient hematopoietic progenitor cells (HPCs) gave rise to B cells both in vitro and in vivo when a wild-type (WT) IL-7Rα chain was introduced; however, no B cells were observed under the same conditions from IL-7Rα-deficient HPCs with introduction of the exogenous IL-7Rα subunit, which lacked the amino acid region at positions 414⁻441 (d414⁻441 mutant). Signal transducer and activator of transcription 5 (STAT5) was phosphorylated in cells with the d414⁻441 mutant, similar to that in WT cells, in response to IL-7 stimulation. In contrast, more truncated STAT5 (tSTAT5) was generated in cells with the d414⁻441 mutant than in WT cells. Additionally, the introduction of exogenous tSTAT5 blocked B lymphopoiesis but not myeloid cell development from WT HPCs in vivo. These results suggested that amino acids 414⁻441 in the IL-7Rα chain formed a critical subdomain necessary for the supportive roles of IL-7 in B-cell development.


Assuntos
Linfócitos B/metabolismo , Diferenciação Celular , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Linfócitos B/citologia , Diferenciação Celular/genética , Proliferação de Células , Citoplasma/metabolismo , Interleucina-7/metabolismo , Subunidade alfa de Receptor de Interleucina-7/química , Subunidade alfa de Receptor de Interleucina-7/genética , Ativação Linfocitária , Mutação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Transporte Proteico , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais
13.
Nutr Res ; 55: 81-93, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29914631

RESUMO

Calorie restriction (CR), also known as energy restriction, has been shown to have a deleterious impact on both adult and aged mouse survival during influenza virus infection. Natural killer (NK) cell phenotypic differences contribute to increased susceptibility of adult CR mice. We hypothesized NK cell phenotype from adult and aged C57Bl/6 mice fed NIH-31 diet ad libitum (AL) would be different from NK cell phenotype from adult and aged mice fed NIH-31/NIA fortified diet at 40% CR. We hypothesized NK cell phenotype from mice consuming 40% CR initiated at 20 months of age would not be different from 40% CR initiated at 3 months of age. We initiated the 40% restriction either at the standard 12 weeks of age or at 78 weeks of age. NK cells were isolated and quantified from various tissues using flow cytometry. Aged CR mice had significantly reduced levels of terminally mature (CD27-CD11b+) NK cells, increased expression of the immature marker CD127, and decreased expression of the mature marker DX5. Total number of NK cells among cells was significantly lower in the lung and spleen of old-onset aged CR mice compared to aged AL mice, while there was no significant difference between young-onset aged CR and aged AL mice. Old-onset aged CR mice had significantly less early mature (DX5+ and CD27+CD11b+) NK cells compared to young-onset aged CR and aged AL fed mice. Overall, we found that CR in aged mice is detrimental to maturation of NK cells, which is exacerbated when CR is initiated in old age.


Assuntos
Envelhecimento/fisiologia , Restrição Calórica , Ingestão de Energia , Células Matadoras Naturais/metabolismo , Pulmão/metabolismo , Baço/metabolismo , Fatores Etários , Animais , Antígenos CD11/metabolismo , Citometria de Fluxo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
14.
Transpl Immunol ; 50: 34-42, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29885905

RESUMO

Models of infection have shaped our understanding of programmed memory T cell differentiation, yet whether these models apply to memory programming in the context of transplantation has yet to be defined. Previous work has identified differences in the response of antigen-specific CD8+ T cells to cognate antigen based on the environment in which the antigen is presented. Thus, we hypothesized that programming of antigen specific CD8+ T cells responding to graft and pathogen may be dissimilar. Here we find that antigen-specific CD8+ T cells primed by a skin graft contract faster than those primed by gammaherpesvirus (gHV), yet are able to expand more rapidly upon rechallenge. Moreover, graft-primed antigen-specific CD8+ T cells exhibited higher frequencies of cells secreting IL-2 and demonstrate lower expression of KLRG-1, which are qualities suggestive of increased recall potential. Additionally, the expression of CD127 at a memory time point suggests graft-elicited CD8+ antigen specific T cells are maintained in a less terminally-differentiated state compared to gHV-elicited CD8+ antigen specific T cells, despite fewer cells being present at that time point. Taken together, our findings suggest that the surface marker expression and functional profiles of T cells depends on the priming conditions and may be used to predict immunologic risk following transplantation after traditional allosensitization or heterologous immune priming.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Gammaherpesvirinae/imunologia , Rejeição de Enxerto/imunologia , Infecções por Herpesviridae/imunologia , Transplante de Pele , Animais , Antígenos Virais/imunologia , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Memória Imunológica , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Isoantígenos/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores Imunológicos/metabolismo
15.
J Immunol Res ; 2018: 4501273, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29850628

RESUMO

We have shown that in the human peripheral blood cells, the innate immunity protein Tag7 can activate a subpopulation of CD3+CD4+CD25+ cells, which have antitumor activity. These cells can induce lysis of HLA-negative tumor cell lines. The Hsp70 stress molecule on the surface of the tumor cells is used as a recognition target, while the Tag7 protein on the lymphocyte membrane acts as a receptor for Hsp70. We have also demonstrated that this subpopulation of the CD4+CD25+ cells is CD127 positive and hence is not the Treg cells. Our data suggest that this subpopulation of cells is identical to the CD4+CD25+ lymphocytes, which are activated in the leukocyte pool by the IL-2 cytokine.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Citocinas/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Neoplasias Experimentais/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Antígenos de Neoplasias/imunologia , Complexo CD3/metabolismo , Diferenciação Celular , Proliferação de Células , Citotoxicidade Imunológica , Células HeLa , Humanos , Imunidade Inata , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Células K562 , Camundongos
16.
Int J Radiat Oncol Biol Phys ; 101(5): 1222-1225, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29859792

RESUMO

PURPOSE: Irradiation may have significant immunomodulatory effects that impact tumor response and could potentiate immunotherapeutic approaches. The purposes of this study were to prospectively investigate circulating lymphoid cell population fractions during hypofractionated proton therapy (HPT) in blood samples of liver cancer patients and to explore their association with survival. METHODS AND MATERIALS: We collected serial blood samples before treatment and at days 8 and 15 of HPT from 43 patients with liver cancer-22 with hepatocellular carcinoma (HCC) and 21 with intrahepatic cholangiocarcinoma (ICC)-enrolled in a phase 2 clinical trial. All patients received 15 fractions of proton therapy to a median dose of 58 Gy (relative biological effectiveness). We used flow cytometry to measure the changes in the fractions of total CD3+, CD4+, and CD8+ T cells; CD4+ CD25+ T cells; CD4+ CD127+ T cells; CD3+ CD8+ CD25+ activated cytotoxic T lymphocytes (CTLs); and CD3- CD56+ natural killer cells. RESULTS: With a median follow-up period of 42 months, median overall survival (OS) in the study cohort was 30.6 months for HCC and 14.5 months for ICC patients. Longer OS was significantly correlated with greater CD4+ CD25+ T-cell (P = .003) and CD4+ CD127+ T-cell (P = .01) fractions at baseline only in ICC patients. In HCC patients, the fraction of activated CTLs mid treatment (at day 8) was significantly associated with OS (P = .007). These findings suggest a differential relevance of immunomodulation by HPT in these liver cancers. CONCLUSIONS: Antitumor immunity may depend on maintenance of a sufficiently high number of activated CTLs during HPT in HCC patients and CD4+ CD25+ T cells and CD4+ CD127+ T cells prior to treatment in ICC patients. These results could guide the design of future studies to determine the optimal treatment schedules when combining irradiation with specific immunotherapy approaches.


Assuntos
Carcinoma Hepatocelular/radioterapia , Colangiocarcinoma/radioterapia , Imunoterapia/métodos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/radioterapia , Linfócitos T/citologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Complexo CD3/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Carcinoma Hepatocelular/sangue , Colangiocarcinoma/sangue , Feminino , Seguimentos , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Células Matadoras Naturais/citologia , Subpopulações de Linfócitos , Masculino , Pessoa de Meia-Idade , Terapia com Prótons , Linfócitos T/metabolismo , Fatores de Tempo , Resultado do Tratamento
17.
Biosci Rep ; 38(3)2018 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-29720427

RESUMO

The long-term chronic inflammation of cervical intraepithelial neoplasia (CIN) induces the initiation and progression of cervical cancer. Long non-coding RNAs (LncRNAs) are being identified to be involved into inflammation and carcinogenesis and could function as cancer biomarkers in clinical. However, the significance of inflammation-related LncRNA (e.g. LncRNA-IL7R) in cervical cancer is limited. We, here, investigated the clinical role of inflammation-related LncRNA-IL7R (Lnc-IL7R) in healthy cervical tissue (n=15), CIN 1/2/3 (n=35), cervical cancer (n=70), and clarified its function via knockdown in vitro and in vivo The results showed that the expression of Lnc-IL7R was increased from normal tissues to neoplastic lesions and cervical cancer. Up-regulated Lnc-IL7R positively correlated to tumor size, International Federation of Gynaecology and Obstetrics (FIGO) stage, and lymph node metastasis (LNM). Patients with high expression of Lnc-IL7R had poor prognosis with short overall survival (OS) time, and Cox regression analysis revealed that Lnc-IL7R could be independent prognostic factor for cervical cancer. Moreover, knockdown of Lnc-IL7R by two different siRNAs in cervical cancer cell lines Hela and SiHa induced impaired cell vitality and caspase-3-dependent apoptosis in vitro Furthermore, inhibition of Lnc-IL7R in vivo significantly restricted the tumor growth with decreased expressions of proliferation index Ki-67 and Lnc-IL7R These data indicated that Lnc-IL7R predicts a poor clinical outcome of cervical cancer patients, and knockdown of Lnc-IL7R is amenable to the treatment of cervical cancer.


Assuntos
Biomarcadores Tumorais/genética , Neoplasia Intraepitelial Cervical/genética , Regulação Neoplásica da Expressão Gênica , Subunidade alfa de Receptor de Interleucina-7/genética , RNA Longo não Codificante/genética , Neoplasias do Colo do Útero/genética , Adulto , Animais , Biomarcadores Tumorais/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Estudos de Casos e Controles , Neoplasia Intraepitelial Cervical/complicações , Neoplasia Intraepitelial Cervical/metabolismo , Neoplasia Intraepitelial Cervical/mortalidade , Feminino , Células HeLa , Xenoenxertos , Humanos , Inflamação , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Metástase Linfática , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , RNA Longo não Codificante/agonistas , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Estudos Retrospectivos , Análise de Sobrevida , Neoplasias do Colo do Útero/etiologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/mortalidade
18.
Immunol Cell Biol ; 96(10): 1035-1048, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29768737

RESUMO

CD8+ T-regulatory (Treg) cells are emerging as crucial components of immune system. Previous studies have reported the presence of FOXP3+ CD8+ Treg cells, similar to CD4+ Tregs, in cancer patients which produce high levels of the immunosuppressive cytokines, IL10 and TGFß. At an early stage of tumor development, we have identified a subset of FOXP3- CD8+ CD25+ KIR+ CD127- Treg-like cells, which are IFNγ+ . However, this early-induced CD8+ CD25+ CD127- T-cell subset is certainly distinct from the IFNγ+ CD8+ T-effector cells. These CD8+ CD25+ CD127- T cells express other FOXP3- CD8+ Treg cell signature markers, and can selectively suppress autoreactive HLA-E+ TFH cells as well as tumor-induced CD4+ Treg cells. In contrast to FOXP3+ CD8+ Tregs, this subset does not inhibit effector T-cell proliferation or their functions as they are HLA-E- . Adoptive transfer of this early-CD8+ Treg-like subset restrained tumor growth and inhibited CD4+ Treg generation that impedes the immune surveillance and impairs cancer immunotherapy. At the late stage of tumor development, when CD4+ Treg cells dominate the tumor-microenvironment, CD4+ Tregs mediate the clonal deletion of these tumor-suppressive FOXP3- IFNγ+ CD8+ CD25+ CD127- T cells and ensure tumor immune evasion. Our findings suggest that at an early stage of the tumor, this tumor-induced IFNγ-producing FOXP3- CD8+ CD25+ CD127- T-cell subset can potentiate immune surveillance by targeting HLA-E-restricted CD4+ Treg cells while leaving the effector T-cell population unaffected. Hence, manipulating their profile can open up a new avenue in cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Citocinas/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Vigilância Imunológica , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Modelos Biológicos , Neoplasias/patologia , Fenótipo , Receptores KIR/metabolismo , Evasão Tumoral , Microambiente Tumoral
19.
J Cell Mol Med ; 22(7): 3353-3363, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29566311

RESUMO

In schistosomiasis japonica and mansoni, parasite eggs trapped in host liver elicit severe liver granulomatous inflammation that subsequently leads to periportal fibrosis, portal hypertension, haemorrhage or even death. Macrophages are critical for granuloma formation and the development of liver fibrosis during schistosomiasis. However, whether the aberrant regulation of macrophage autophagy has an effect on the development of liver immunopathology in schistosomiasis remains to be elucidated. In this study, we showed that Schistosoma japonicum (S. japonicum) egg antigen (SEA)-triggered macrophage autophagy limited the development of pathology in host liver. However, engagement of IL-7 receptor (IL-7R/CD127) on macrophages by S. japonicum infection-induced IL-7 significantly suppressed SEA-triggered macrophage autophagy, which led to an enhanced liver pathology. In addition, anti-IL-7 neutralizing antibody or anti-CD127 blocking antibody treatment increased macrophage autophagy and suppressed liver pathology. Finally, we demonstrated that IL-7 protects macrophage against SEA-induced autophagy through activation of AMP-activated protein kinase (AMPK). Our study reveals a novel role for IL-7 in macrophage autophagy and identifies AMPK as a novel downstream mediator of IL-7-IL-7R signalling and suggests that manipulation of macrophage autophagy by targeting IL-7-IL-7R signalling may have the potential to lead to improved treatment options for liver pathogenesis in schistosomiasis.


Assuntos
Interleucina-7/metabolismo , Fígado/patologia , Macrófagos Peritoneais/patologia , Esquistossomose Japônica/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Autofagia , Feminino , Interações Hospedeiro-Parasita/fisiologia , Interleucina-7/genética , Interleucina-7/farmacologia , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Fígado/metabolismo , Fígado/parasitologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Camundongos Endogâmicos C57BL , Schistosoma japonicum/patogenicidade , Esquistossomose Japônica/metabolismo
20.
J Clin Invest ; 128(3): 916-930, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29376889

RESUMO

Acute graft-versus-host disease (GVHD) represents a severe, T cell-driven inflammatory complication following allogeneic hematopoietic cell transplantation (allo-HCT). GVHD often affects the intestine and is associated with a poor prognosis. Although frequently detectable, proinflammatory mechanisms exerted by intestinal tissue-infiltrating Th cell subsets remain to be fully elucidated. Here, we show that the Th17-defining transcription factor basic leucine zipper transcription factor ATF-like (BATF) was strongly regulated across human and mouse intestinal GVHD tissues. Studies in complete MHC-mismatched and minor histocompatibility-mismatched (miHA-mismatched) GVHD models revealed that BATF-expressing T cells were functionally indispensable for intestinal GVHD manifestation. Mechanistically, BATF controlled the formation of colon-infiltrating, IL-7 receptor-positive (IL-7R+), granulocyte-macrophage colony-stimulating factor-positive (GM-CSF+), donor T effector memory (Tem) cells. This T cell subset was sufficient to promote intestinal GVHD, while its occurrence was largely dependent on T cell-intrinsic BATF expression, required IL-7-IL-7R interaction, and was enhanced by GM-CSF. Thus, this study identifies BATF-dependent pathogenic GM-CSF+ effector T cells as critical promoters of intestinal inflammation in GVHD and hence putatively provides mechanistic insight into inflammatory processes previously assumed to be selectively Th17 driven.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Doença Enxerto-Hospedeiro/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Intestinos/patologia , Subpopulações de Linfócitos T/metabolismo , Animais , Biópsia , Colo/patologia , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Inflamação , Intestinos/imunologia , Complexo Principal de Histocompatibilidade , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Prognóstico , Transplante Homólogo
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