RESUMEN
Regulatory T (Treg) cells are a specialized subset of T cells possessing immunosuppressive functions indispensable for the maintenance of self-tolerance and pregnancy. However, how functional Treg cells dynamically change and are engaged in feto-maternal tolerance during human pregnancy is still unclear. Recent studies have shown that functionally distinct and immunosuppressive subsets of Treg cells, i.e., effector Treg (eTreg) and naïve Treg (nTreg) cells, can be delineated by combinations of molecular markers and that their proportions differ in normal and disease states. In this study, we examined how the proportion of eTreg and nTreg cells in peripheral blood changes in the 1st, 2nd, and 3rd trimesters of pregnancy and the postpartum period. During the 2nd trimester the proportion of eTreg cells was reduced while nTreg cells was increased. This pattern was maintained throughout the 3rd trimester of pregnancy. The kinetics of eTreg reduction highly correlated with migration of eTreg cells into feto-maternal interface while stable nTreg proportion paralleled with their expression of the anti-apoptotic molecule Bcl-2 and production of thymic emigrant naïve Treg cells. These results suggest that further studies on divergence of functional Treg proportions will be helpful for predicting instability of pregnancy.
Asunto(s)
Embarazo/inmunología , Subgrupos de Linfocitos T/microbiología , Linfocitos T Reguladores/inmunología , Timocitos/inmunología , Adulto , Femenino , Factores de Transcripción Forkhead/metabolismo , Humanos , Tolerancia Inmunológica , Trimestres del Embarazo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Neurotuberculosis is one of the commonest HIV associated opportunistic infections of the central nervous system in India. HIV-TB coinfection may lead to altered frequencies of T cells, thereby influencing the course and progression of the disease. METHODS: We examined the frequencies of T cell subsets in HIV infected individuals with neurotuberculosis (HIV+nTB+) as compared to individuals with HIV associated systemic TB (HIV+sTB+), asymptomatic HIV (HIV+TB-), non-HIV neuro TB (HIV-nTB+), non-HIV systemic TB (HIV-sTB+), and healthy controls (HIV-TB-). Activation and senescence profiles of CD4 and CD8 T cells and memory subsets in peripheral blood mononuclear cells were studied by flow cytometry. RESULTS: The significant observations among the T cell subsets in HIV+nTB+ were: (1) Naïve T cells: decreased CD4 T cells compared to HIV-sTB+ (P = 0.005); decreased CD8 T cells compared to HIV-nTB+ and HIV-TB- (P ≤ 0.007), (2) Memory T cells: expanded CD4 TEMRA cells compared to HIV-nTB+, HIV-sTB+, and HIV-TB- (P ≤ 0.003); expanded CD8 TEMRA cells compared to HIV-nTB+ and HIV-TB- (P ≤ 0.005), (3) Activated T cells: higher CD4 T cells compared to HIV-nTB+, HIV-sTB+, and HIV-TB- (P ≤ 0.004); higher CD8 T cells compared to HIV + TB-, HIV-nTB+, HIV-sTB+, and HIV-TB- (P ≤ 0.001), and (4) Senescent T cells: increased CD8 T cells compared to HIV-nTB+ and HIV-TB- groups (P = 0.000). CONCLUSIONS: Increased activation compared to HIV+TB-, HIV-nTB+, HIV-sTB+, and HIV-TB- groups and increased senescence compared to HIV-nTB+ and HIV-TB- groups were observed in CD8 T cells in HIV+nTB+, suggesting that the frequencies of these T cell subsets are altered to a greater extent in these individuals. © 2018 International Clinical Cytometry Society.
Asunto(s)
Citometría de Flujo , Infecciones por VIH/diagnóstico , Leucocitos Mononucleares/ultraestructura , Activación de Linfocitos/inmunología , Adulto , Anciano , Linfocitos T CD4-Positivos/microbiología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/microbiología , Linfocitos T CD8-positivos/virología , Femenino , Infecciones por VIH/microbiología , Infecciones por VIH/patología , Infecciones por VIH/virología , Humanos , India/epidemiología , Leucocitos Mononucleares/microbiología , Leucocitos Mononucleares/patología , Leucocitos Mononucleares/virología , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/patogenicidad , Fenotipo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/microbiología , Subgrupos de Linfocitos T/ultraestructura , Subgrupos de Linfocitos T/virología , Adulto JovenRESUMEN
Since their discovery about 10 years ago, Th9 cells have been increasingly linked to allergic pathologies. Within this review, we summarize the current knowledge on associations between Th9 cells and allergic diseases and acknowledge Th9 cells as important targets in future treatment of allergic diseases. However, until today, it is not fully understood how these Th9 cell responses are modulated. We describe current literature suggesting that these Th9 cell responses might be stimulated by microbial species such as Staphylococcus aureus and Candida albicans, while on the other hand, microbial and dietary compounds such as retinoic acid (RA), butyrate and vitamin D show suppressive capacity on allergy-related Th9 responses. By reviewing this recent research, we provide new insights into the modulating capacity of the microbiota on Th9 cell responses. Consequently, microbial and dietary factors may be used as innovative tools to target Th9 cells in the treatment of allergic diseases. However, further research is needed to elucidate the mechanisms behind these interactions in order to translate this knowledge into clinical allergy settings.
Asunto(s)
Hipersensibilidad/inmunología , Hipersensibilidad/microbiología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/microbiología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/microbiología , Animales , HumanosRESUMEN
IFN-ß essentially modulates the host response against mucocutaneous colonizers and potential pathogens, such as group B Streptococcus (GBS). It has been reported that the dominant signaling cascade driving IFN-ß in macrophages (MΦ) in streptococcal infection is the cGAS-STING pathway, whereas conventional dendritic cells (DC) exploit endosomal recognition by intracellular TLRs. In this study, we revisited this issue by precisely monitoring the phenotypic dynamics in mixed mouse MΦ/DC cultures with GM-CSF, which requires snapshot definition of cellular identities. We identified four mononuclear phagocyte populations, of which two were transcriptionally and morphologically distinct MΦ-DC-like subsets, and two were transitional types. Notably, GBS induced a TLR7-dependent IFN-ß signal only in MΦ-like but not in DC-like cells. IFN-ß induction did not require live bacteria (i.e., the formation of cytolytic toxins), which are essential for IFN-ß induction via cGAS-STING. In contrast to IFN-ß, GBS induced TNF-α independently of TLR7. Subsequent to the interaction with streptococci, MΦ changed their immunophenotype and gained some typical DC markers and DC-like morphology. In summary, we identify IFN-ß formation as part of the antistreptococcal repertoire of GM-CSF differentiated MΦ in vitro and in vivo and delineate their plasticity.
Asunto(s)
Interferón beta/biosíntesis , Macrófagos/inmunología , Macrófagos/metabolismo , Streptococcus/inmunología , Animales , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Inmunofenotipificación , Activación de Macrófagos/genética , Activación de Macrófagos/inmunología , Factor Estimulante de Colonias de Macrófagos/farmacología , Ratones , Modelos Biológicos , Fagocitosis , Infecciones Estreptocócicas/inmunología , Infecciones Estreptocócicas/metabolismo , Infecciones Estreptocócicas/microbiología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/microbiologíaRESUMEN
MAIT cells are an evolutionarily conserved T cell subset recognizing ubiquitous microbial metabolites. Herein, we review recent literature showing that MAIT cells can be divided into type 1 and type 17 subsets, which acquire a tissue resident differentiation program in the thymus and localize in specific tissues. We also discuss the nature and in vivo availability of the different agonist and antagonist MAIT ligands with potential consequences for MAIT cell biology.
Asunto(s)
Inmunidad Mucosa/inmunología , Células T Invariantes Asociadas a Mucosa/inmunología , Células T Asesinas Naturales/inmunología , Subgrupos de Linfocitos T/inmunología , Timo/inmunología , Animales , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/microbiología , Humanos , Activación de Linfocitos/inmunología , Células T Invariantes Asociadas a Mucosa/microbiología , Micosis/inmunología , Micosis/microbiología , Células T Asesinas Naturales/microbiología , Subgrupos de Linfocitos T/microbiología , Timo/microbiologíaRESUMEN
Mucosal-associated Invariant T (MAIT) cells represent a large proportion of T cells in human blood, and are also present throughout the body, being concentrated at mucosal sites. Their high level of conservation throughout mammalian evolution and recognition of conserved microbial antigens, derived from precursors of riboflavin (vitamin B2) biosynthesis, suggest an important role in protective immunity to pathogens. However, the picture that is emerging of MAIT cell immune function is increasingly complex, with numerous correlations of MAIT cell numbers with human diseases, and with recent studies demonstrating their pathogenic potential. The conditions that drive MAIT cell responses towards a protective versus pathogenic role are only beginning to be deciphered and, yet, must be understood for any attempt to harness MAIT cells therapeutically. In this review we summarise our current knowledge of immune protection and pathology driven by MAIT cells, models used to study their role in immunity and steps towards elucidating the immune signals driving these responses.
Asunto(s)
Presentación de Antígeno/inmunología , Inmunidad/inmunología , Células T Invariantes Asociadas a Mucosa/inmunología , Subgrupos de Linfocitos T/inmunología , Inmunidad Adaptativa/inmunología , Animales , Antígenos Bacterianos/inmunología , Helicobacter pylori/inmunología , Helicobacter pylori/fisiología , Humanos , Inmunidad Mucosa/inmunología , Subgrupos de Linfocitos T/microbiologíaRESUMEN
A better knowledge of factors predicting the development of sepsis in patients hospitalized in intensive care unit (ICU) might help deploy more targeted preventive and therapeutic strategies. In addition to the known clinical and demographic predictors of septic syndromes, in this study, we investigated whether measuring T and B lymphocyte subsets upon admission in the ICU may help individualize the prediction of ensuing sepsis during ICU stay. Between May 2015 and December 2016, we performed a prospective cohort study evaluating peripheral blood lymphocyte T-CD4+ (T-helper cells), T-CD8+ (cytotoxic T-cells), T-CD56 + (natural killer cells), and T-CD19+ (B-lymphocytes), using flow cytometry on blood samples collected 2 days after admission in the ICU. We enrolled 176 patients, 65.3% males, with mean age of 61.1 ± 15.4 years. At univariate analyses, higher percentages of CD19 B-cells were significantly associated with ensuing sepsis (20.5% (15.7-27.7)% vs 16.9% (11.3-22)%, P = 0.0001), whereas median interquartile range (IQR) proportions of CD4 T-cells (41.2% (33.4-50.6)% vs 40% (35-47)%, P = 0.5), CD8 T-cells (21.1% (15.8-28.2)% vs 19.6% (14.6-25.1)%, P = 0.2) and CD56 T-cells (1.7% (0.9-3.1)% vs 1.45% (0.7-2.3)%, P = 0.4) did not reveal any significant association. An unexpected, highly significant inverse correlation of CD8 T-cells and CD19 B-cells proportions, however, was observed, suggesting that patients with lower CD19 and higher CD8 proportions might be somehow protected from ensuing sepsis. We therefore studied the ability of the CD8/CD19 ratio to predict ensuing sepsis in our sample. In final models of multivariate logistic regression, the following independent associations were found: previous antibiotic exposure (odds ratio (OR): 3.8 (95% confidence interval (CI): 1.35-10.87), P = 0.01), isolation of at least one multi-drug resistant organism at any time during ICU stay (OR: 8.4 (95% CI: 3.47-20.6), P < 0.0001), decreasing age (OR: 0.9 (95% CI: 0.93-0.99), P = 0.02) and a CD8/CD19 ratio >2.2 (OR: 10.3 (95% CI: 1.91-55.36), P = 0.007). Our data provide preliminary evidence that immune characterization of critically ill patients on ICU admission may help personalize the prediction of ensuing sepsis during their ICU stay. Further polycentric evaluation of the true potential of this new tool is warranted.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Unidades de Cuidados Intensivos , Admisión del Paciente , Sepsis/inmunología , Subgrupos de Linfocitos T/inmunología , APACHE , Factores de Edad , Anciano , Antibacterianos/efectos adversos , Subgrupos de Linfocitos B/microbiología , Biomarcadores/sangre , Femenino , Citometría de Flujo , Interacciones Huésped-Patógeno , Humanos , Inmunofenotipificación/métodos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Fenotipo , Valor Predictivo de las Pruebas , Datos Preliminares , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Sepsis/sangre , Sepsis/diagnóstico , Sepsis/microbiología , Factores Sexuales , Subgrupos de Linfocitos T/microbiologíaRESUMEN
In the gut, various subsets of intraepithelial T cells (IELs) respond to self or non-self-antigens derived from the body, diet, commensal and pathogenic microbiota. Dominant subset of IELs in the small intestine are TCRαßCD8αα+ cells, which are derived from immature thymocytes that express self-reactive TCRs. Although most of TCRαßCD8αα+ IELs are thymus-derived, their repertoire adapts to microbial flora. Here, using high throughput TCR sequencing we examined how clonal diversity of TCRαßCD8αα+ IELs changes upon exposure to commensal-derived antigens. We found that fraction of CD8αα+ IELs and CD4+ T cells express identical αßTCRs and this overlap raised parallel to a surge in the diversity of microbial flora. We also found that an opportunistic pathogen (Staphylococcus aureus) isolated from mouse small intestine specifically activated CD8αα+ IELs and CD4+ derived T cell hybridomas suggesting that some of TCRαßCD8αα+ clones with microbial specificities have extrathymic origin. We also report that CD8ααCD4+ IELs and Foxp3CD4+ T cells from the small intestine shared many αßTCRs, regardless whether the later subset was isolated from Foxp3CNS1 sufficient or Foxp3CNS1 deficient mice that lacks peripherally-derived Tregs. Overall, our results imply that repertoire of TCRαßCD8αα+ in small intestine expends in situ in response to changes in microbial flora.
Asunto(s)
Antígenos Bacterianos/inmunología , Antígenos CD8/metabolismo , Intestino Delgado/inmunología , Linfocitos Intraepiteliales/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Animales , Antígenos CD8/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/microbiología , Diferenciación Celular , Femenino , Intestino Delgado/metabolismo , Intestino Delgado/microbiología , Linfocitos Intraepiteliales/metabolismo , Linfocitos Intraepiteliales/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Infecciones Estafilocócicas/metabolismo , Infecciones Estafilocócicas/microbiología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/microbiologíaRESUMEN
BACKGROUND: Guillain-Barré syndrome (GBS) is a rare, autoimmune-mediated disease. The use of Bifidobacterium is reportedly effective in alleviating GBS since they act by regulating T helper (Th) cells. OBJECTIVES: In this study, we explored the differentiation of T helper cell subsets in patients with GBS. We also evaluated the effect of GBS on Bifidobacterium levels in patients and the likely protective influence of this bacterium in alleviating the disease in an animal model. MATERIALS AND METHODS: We used flow cytometry, and real-time polymerase chain reaction (PCR) to determine the T cell subsets differentiation among 30 GBS patients and 20 healthy controls (HC). The concentration of Bifidobacterium was assayed by real-time PCR. Experimental autoimmune neuritis (EAN) animal model was established to support the protective role of Bifidobacterium in GBS. RESULTS: The expression of Th cells, Th2 and Th17 in the patients was significantly higher than that in the HC, while Treg cells decreased substantially. Moreover, the levels of Bifidobacterium in the GBS patients were considerably lower than those in the HC, the concentration of Bifidobacterium correlating with Th2 and Th17 subsets negatively. Treatment with Bifidobacterium significantly reduced the levels of Th2 and Th17 and promoted the levels of Treg cells. CONCLUSIONS: We concluded from this study that Bifidobacterium alleviated GBS by regulating Th cells, although in-depth studies might be required to fully understand the mechanism of action.
Asunto(s)
Bifidobacterium longum subspecies infantis/inmunología , Terapia Biológica , Síndrome de Guillain-Barré/terapia , Neuritis Autoinmune Experimental/terapia , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Animales , Autoinmunidad , Diferenciación Celular , Células Cultivadas , Femenino , Humanos , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Ratas , Ratas Endogámicas , Subgrupos de Linfocitos T/microbiología , Linfocitos T Reguladores/microbiologíaRESUMEN
BACKGROUND: Human Immunodeficiency Virus (HIV) infection is a risk factor for tuberculosis (TB). Antiretroviral therapy (ART) changed HIV clinical management but it is still unclear how pre-existing HIV/Mycobacterium tuberculosis (Mtb)-specific CD4+ and CD8+ T-cells are restored. AIM: to evaluate the impact of ART and TB therapies on the functional and phenotypic profile of Mtb-specific antigen-response of CD4+ and CD8+ T-cells in prospectively enrolled HIV-TB co-infected patients. METHODS: ART-naïve HIV-infected patients, with or without active TB or latent TB infection (LTBI), were enrolled before and after starting ART and TB therapies. Peripheral blood mononuclear cells (PBMC) were stimulated overnight with Mtb and HIV antigens (GAG). Cytokine expression and phenotype profile were evaluated by flow cytometry. Cytomegalovirus (CMV) and staphylococcal enterotoxin B (SEB) were also used. RESULTS: The median of absolute number of CD4+ T-cells increased after ART and TB therapies in all groups analyzed, while the median of absolute number of CD8+ T-cells decreases in HIV and HIV-LTBI groups. Treatments significantly increased the frequency of Mtb-specific CD4+ T-cells in the HIV-LTBI (pâ¯=â¯0.015) with a rise of the central memory compartment. The magnitude of the CD4+ T-cell response to HIV-GAG significantly increased in active TB (pâ¯=â¯0.03), whereas the magnitude of CMV-specific CD4+ T-cell response decreased in all the groups. Similarly, the treatments increased the number of Mtb-specific CD8+ responders in both HIV-LTBI and HIV-TB groups, whereas the phenotype distribution was dependent on the antigens used and on the stage of infection/disease. CONCLUSIONS: After therapies the median of absolute number and the proportion of CD4+ T-cells increased in all groups whereas the median of absolute count and proportion of CD8+ T-cells decreased in the HIV and HIV-LTBI subjects. Interestingly, an increased frequency of CD4+ T-cell response to RD1 proteins in HIV-LTBI subjects was found. These results contribute to a better understanding of the effect of ART and TB therapies on the modulation of Mtb-specific CD4+ and CD8+ T-cells subsets.
Asunto(s)
Antirretrovirales/uso terapéutico , Antituberculosos/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Coinfección , Infecciones por VIH , Tuberculosis , Adulto , Antígenos Bacterianos/inmunología , Linfocitos T CD4-Positivos/microbiología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/microbiología , Linfocitos T CD8-positivos/virología , Coinfección/tratamiento farmacológico , Coinfección/inmunología , Citocinas/metabolismo , Femenino , Antígenos VIH/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Humanos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Masculino , Mycobacterium tuberculosis/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/microbiología , Subgrupos de Linfocitos T/virología , Tuberculosis/tratamiento farmacológico , Tuberculosis/inmunologíaRESUMEN
CD4+ T cells are critical regulators of the adaptive immune system and have diverse roles in regulating responses to the broad array of microbes encountered. Appropriate execution of their effector function requires precise and coordinated migration of these cells to specific lymphoid niches and peripheral sites. This migration is largely controlled by dynamic expression of chemokine receptors and the discrete functions of distinct subsets of CD4+ T cells can often be determined from their expression of specific chemokine receptors. In this chapter, we discuss recent advances in the subset-specific homing of distinct T helper populations, focusing on new insights stemming from the increased diversity and plasticity now observed among CD4+ T cells as well as how chemokine receptors can govern T cell-fate decisions. We also discuss current understanding of CD4+ memory T cells with reference to their diversification based on chemokine receptor expression.
Asunto(s)
Infecciones Bacterianas/inmunología , Linfocitos T CD4-Positivos/inmunología , Movimiento Celular/inmunología , Quimiocinas/inmunología , Receptores de Quimiocina/inmunología , Subgrupos de Linfocitos T/inmunología , Inmunidad Adaptativa , Animales , Infecciones Bacterianas/genética , Infecciones Bacterianas/microbiología , Infecciones Bacterianas/patología , Linfocitos T CD4-Positivos/microbiología , Quimiocinas/genética , Células Dendríticas/inmunología , Células Dendríticas/microbiología , Regulación de la Expresión Génica , Humanos , Memoria Inmunológica , Activación de Linfocitos , Receptores de Quimiocina/genética , Transducción de Señal , Subgrupos de Linfocitos T/microbiologíaRESUMEN
Coinfection with HIV is the single greatest risk factor for reactivation of latent Mycobacterium tuberculosis infection (LTBI) and progression to active tuberculosis disease. HIV-associated dysregulation of adaptive immunity by depletion of CD4 Th cells most likely contributes to loss of immune control of LTBI in HIV-infected individuals, although the precise mechanisms whereby HIV infection impedes successful T cell-mediated control of M. tuberculosis have not been well defined. To further delineate mechanisms whereby HIV impairs protective immunity to M. tuberculosis, we evaluated the frequency, phenotype, and functional capacity of M. tuberculosis-specific CD4 T cells in HIV-infected and HIV-uninfected adults with LTBI. HIV infection was associated with a lower total frequency of cytokine-producing M. tuberculosis-specific CD4 T cells, and preferential depletion of a discrete subset of M. tuberculosis-specific IFN-γ+IL-2-TNF-α+ CD4 T cells. M. tuberculosis-specific CD4 T cells in HIV-infected individuals expressed significantly higher levels of Ki67, compared with HIV-uninfected individuals, thus indicating recent activation and turnover of these cells in vivo. The ex vivo proliferative capacity of M. tuberculosis-specific CD4 T cells was markedly impaired in HIV-infected individuals, compared with HIV-uninfected individuals. Moreover, HIV infection was associated with increased M. tuberculosis Ag-induced CD4 T cell death ex vivo, indicating a possible mechanism contributing to impaired proliferative capacity of M. tuberculosis-specific CD4 T cells in HIV-infected individuals. These data provide new insights into the parameters of M. tuberculosis-specific CD4 T cell immunity that are impaired in HIV-infected individuals with LTBI, which may contribute to their increased risk of developing active tuberculosis disease.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Mycobacterium tuberculosis/inmunología , Subgrupos de Linfocitos T/inmunología , Tuberculosis/inmunología , Latencia del Virus , Adolescente , Adulto , Antígenos Bacterianos/inmunología , Apoptosis , Linfocitos T CD4-Positivos/microbiología , Linfocitos T CD4-Positivos/virología , Proliferación Celular , Células Cultivadas , Coinfección , Femenino , Humanos , Inmunofenotipificación , Interferón gamma/metabolismo , Interleucina-2/metabolismo , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Subgrupos de Linfocitos T/microbiología , Subgrupos de Linfocitos T/virología , Latencia del Virus/inmunología , Adulto JovenAsunto(s)
Alergia e Inmunología/historia , Mycobacterium tuberculosis/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T/inmunología , Tuberculosis/inmunología , Traslado Adoptivo , Animales , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Enfermedad Crónica , Ciclofosfamida/farmacología , Femenino , Historia del Siglo XX , Humanos , Inmunosupresores/farmacología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Mycobacterium tuberculosis/patogenicidad , Subgrupos de Linfocitos T/microbiología , Subgrupos de Linfocitos T/trasplante , Linfocitos T/microbiología , Linfocitos T/trasplanteRESUMEN
Dynamic changes in the expression of transcription factors (TFs) can influence the specification of distinct CD8+ T cell fates, but the observation of equivalent expression of TFs among differentially fated precursor cells suggests additional underlying mechanisms. Here we profiled the genome-wide histone modifications, open chromatin and gene expression of naive, terminal-effector, memory-precursor and memory CD8+ T cell populations induced during the in vivo response to bacterial infection. Integration of these data suggested that the expression and binding of TFs contributed to the establishment of subset-specific enhancers during differentiation. We developed a new bioinformatics method using the PageRank algorithm to reveal key TFs that influence the generation of effector and memory populations. The TFs YY1 and Nr3c1, both constitutively expressed during CD8+ T cell differentiation, regulated the formation of terminal-effector cell fates and memory-precursor cell fates, respectively. Our data define the epigenetic landscape of differentiation intermediates and facilitate the identification of TFs with previously unappreciated roles in CD8+ T cell differentiation.
Asunto(s)
Linfocitos T CD8-positivos/fisiología , Epigénesis Genética , Listeriosis/inmunología , Receptores de Glucocorticoides/metabolismo , Subgrupos de Linfocitos T/fisiología , Factor de Transcripción YY1/metabolismo , Animales , Linfocitos T CD8-positivos/microbiología , Diferenciación Celular/genética , Biología Computacional , Elementos de Facilitación Genéticos/genética , Perfilación de la Expresión Génica , Histonas/metabolismo , Memoria Inmunológica/genética , Ratones , Ratones Endogámicos C57BL , Receptores de Glucocorticoides/genética , Subgrupos de Linfocitos T/microbiología , Factor de Transcripción YY1/genéticaRESUMEN
γ9δ2 T cells provide a natural bridge between innate and adaptive immunity, rapidly and potently respond to pathogen infection in mucosal tissues, and are prominently induced by both tuberculosis (TB) infection and bacillus Calmette Guérin (BCG) vaccination. Mycobacterium-expanded γ9δ2 T cells represent only a subset of the phosphoantigen {isopentenyl pyrophosphate [IPP] and (E)-4-hydroxy-3-methyl-but-2-enylpyrophosphate [HMBPP]}-responsive γ9δ2 T cells, expressing an oligoclonal set of T cell receptor (TCR) sequences which more efficiently recognize and inhibit intracellular Mycobacterium tuberculosis infection. Based on this premise, we have been searching for M. tuberculosis antigens specifically capable of inducing a unique subset of mycobacterium-protective γ9δ2 T cells. Our screening strategy includes the identification of M. tuberculosis fractions that expand γ9δ2 T cells with biological functions capable of inhibiting intracellular mycobacterial replication. Chemical treatments of M. tuberculosis whole-cell lysates (MtbWL) ruled out protein, nucleic acid, and nonpolar lipids as the M. tuberculosis antigens inducing protective γ9δ2 T cells. Mild acid hydrolysis, which transforms complex carbohydrate to monomeric residues, abrogated the specific activity of M. tuberculosis whole-cell lysates, suggesting that a polysaccharide was required for biological activity. Extraction of MtbWL with chloroform-methanol-water (10:10:3) resulted in a polar lipid fraction with highly enriched specific activity; this activity was further enriched by silica gel chromatography. A combination of mass spectrometry and nuclear magnetic resonance analysis of bioactive fractions indicated that 6-O-methylglucose-containing lipopolysaccharides (mGLP) are predominant components present in this active fraction. These results have important implications for the development of new immunotherapeutic approaches for prevention and treatment of TB.
Asunto(s)
Glucolípidos/inmunología , Activación de Linfocitos/inmunología , Mycobacterium tuberculosis/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Subgrupos de Linfocitos T/inmunología , Tuberculosis/inmunología , Inmunidad Adaptativa/inmunología , Animales , Antígenos Bacterianos/inmunología , Hemiterpenos/inmunología , Metilglucósidos/inmunología , Compuestos Organofosforados/inmunología , Polisacáridos/inmunología , Subgrupos de Linfocitos T/microbiología , Tuberculosis/microbiologíaRESUMEN
Bacterial vaginosis (BV) is the most common female reproductive tract infection and is associated with an increased risk of acquiring and transmitting HIV by a mechanism that is not well understood. Gamma delta (GD) T cells are essential components of the adaptive and innate immune system, are present in the female reproductive tract, and play an important role in epithelial barrier protection. GD1 cells predominate in the mucosal tissue and are important in maintaining mucosal integrity. GD2 cells predominate in peripheral blood and play a role in humoral immunity and in the immune response to pathogens. HIV infection is associated with changes in GD T cells frequencies in the periphery and in the female reproductive tract. The objective of this study is to evaluate if changes in vaginal flora occurring with BV are associated with changes in endocervical GD T cell responses, which could account for increased susceptibility to HIV. Seventeen HIV-infected (HIV+) and 17 HIV-uninfected (HIV-) pre-menopausal women underwent collection of vaginal swabs and endocervical cytobrushes. Vaginal flora was assessed using the Nugent score. GD T cells were assessed in cytobrush samples by flow cytometry. Median Nugent score was 5.0 and 41% of women had abnormal vaginal flora. In HIV uninfected women there was a negative correlation between Nugent score and cervical GD1 T cells (b for interaction = - 0.176, p<0.01); cervical GD1 T cells were higher in women with normal vaginal flora than in those with abnormal flora (45.00% vs 9.95%, p = 0.005); and cervical GD2 T cells were higher in women with abnormal flora than in those with normal flora (1.70% vs 0.35%, p = 0.023). GD T cells in the genital tract are protective (GD1) and are targets for HIV entry (GD2). The decrease in cervical GD1 and increase in GD2 T cells among women with abnormal vaginal flora predisposes women with BV to HIV acquisition. We propose to use GD T cell as markers of female genital tract vulnerability to HIV.
Asunto(s)
Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Infecciones del Sistema Genital/inmunología , Subgrupos de Linfocitos T/inmunología , Vaginosis Bacteriana/inmunología , Adulto , Bacterias/clasificación , Bacterias/crecimiento & desarrollo , Bacterias/inmunología , Recuento de Linfocito CD4 , Cuello del Útero/inmunología , Cuello del Útero/microbiología , Estudios Transversales , Susceptibilidad a Enfermedades/inmunología , Femenino , Florida , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Interacciones Huésped-Patógeno/inmunología , Humanos , Microbiota/inmunología , Microbiota/fisiología , Dinámica Poblacional , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Infecciones del Sistema Genital/microbiología , Factores de Riesgo , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/microbiología , Vaginosis Bacteriana/microbiologíaRESUMEN
INTRODUCTION: The study was designed to assess the role of some important immunologic factors with regards to both laboratory results and clinical symptoms in patients with confirmed Lyme disease. Additional examinations were carried out for co-infections with a number of tick-borne pathogens. MATERIAL AND METHODS: The study group consisted of 54 patients with Lyme disease and a group of 21 healthy controls. Serology of co-infections with Anaplasma phagocytophilum, Bartonella spp. and Babesia microti was carrieed out in all patients. Blood samples were stained using the whole-blood lysis method and analyzed concurrently on a flow cytometer FACSCalibur. Directly conjugated anti-human monoclonal antibodies against CD3, CD4, CD8, CD16, CD56, HLA-DR and CD69 were used. RESULTS: No significant differences were observed with respect to thepretreatment level of CD4+ and CD8+ cells. In patients with symptoms relief and symptoms persistence, lower percentages of CD4+ and CD8+ cells were found, but with no statistical dependence. In the study group, both in patients with and without co-infections, pretreatment values of CD16+CD56+ cells did not differ significantly. In patients who did not respond to the treatment, the baseline percentage of NK cells was higher (P<0.01) than in group with clinical improvement, and lower after the treatment, whereas in patients with symptoms relief after the treatment there was an increase in the percentage of NK cells. CONCLUSION: Co-infections with Anaplasma phagocytophilum, Bartonella spp. and Babesia microti had no impact on T-cell percentages in Lyme disease patients. There was a lower baseline percentage of NK cells in patients not responding to antibiotic treatment.
Asunto(s)
Grupo Borrelia Burgdorferi/fisiología , Coinfección/inmunología , Enfermedad de Lyme/inmunología , Subgrupos de Linfocitos T/inmunología , Adulto , Anciano , Anaplasma phagocytophilum/fisiología , Babesia microti/fisiología , Babesiosis/tratamiento farmacológico , Babesiosis/inmunología , Babesiosis/parasitología , Bartonella/fisiología , Infecciones por Bartonella/tratamiento farmacológico , Infecciones por Bartonella/inmunología , Infecciones por Bartonella/microbiología , Coinfección/microbiología , Coinfección/parasitología , Ehrlichiosis/tratamiento farmacológico , Ehrlichiosis/inmunología , Ehrlichiosis/microbiología , Femenino , Humanos , Enfermedad de Lyme/tratamiento farmacológico , Enfermedad de Lyme/microbiología , Masculino , Persona de Mediana Edad , Polonia , Subgrupos de Linfocitos T/microbiología , Subgrupos de Linfocitos T/parasitología , Adulto JovenRESUMEN
The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alterations, influenced by diet, environmental and microbial exposures, and host immunity. Fusobacterium species are part of the human oral and intestinal microbiota. Metagenomic analyses have shown an enrichment of Fusobacterium nucleatum (F. nucleatum) in colorectal carcinoma tissue. Using 511 colorectal carcinomas from Japanese patients, we assessed the presence of F. nucleatum. Our results showed that the frequency of F. nucleatum positivity in the Japanese colorectal cancer was 8.6% (44/511), which was lower than that in United States cohort studies (13%). Similar to the United States studies, F. nucleatum positivity in Japanese colorectal cancers was significantly associated with microsatellite instability (MSI)-high status. Regarding the immune response in colorectal cancer, high levels of infiltrating T-cell subsets (i.e., CD3+, CD8+, CD45RO+, and FOXP3+ cells) have been associated with better patient prognosis. There is also evidence to indicate that molecular features of colorectal cancer, especially MSI, influence T-cell-mediated adaptive immunity. Concerning the association between the gut microbiome and immunity, F. nucleatum has been shown to expand myeloid-derived immune cells, which inhibit T-cell proliferation and induce T-cell apoptosis in colorectal cancer. This finding indicates that F. nucleatum possesses immunosuppressive activities by inhibiting human T-cell responses. Certain microRNAs are induced during the macrophage inflammatory response and have the ability to regulate host-cell responses to pathogens. MicroRNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cell-mediated adaptive immunity through the inhibition of the antigen-presenting capacities of dendritic cells and T-cell proliferation in colorectal cancer cells. Thus, emerging evidence may provide insights for strategies to target microbiota, immune cells and tumor molecular alterations for colorectal cancer prevention and treatment. Further investigation is needed to clarify the association of Fusobacterium with T-cells and microRNA expressions in colorectal cancer.
Asunto(s)
Inmunidad Adaptativa , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/microbiología , Infecciones por Fusobacterium/microbiología , Fusobacterium nucleatum/patogenicidad , Microbioma Gastrointestinal , Inmunidad Innata , Animales , Biomarcadores de Tumor/inmunología , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Infecciones por Fusobacterium/genética , Infecciones por Fusobacterium/inmunología , Infecciones por Fusobacterium/metabolismo , Fusobacterium nucleatum/inmunología , Fusobacterium nucleatum/metabolismo , Interacciones Huésped-Patógeno , Humanos , Activación de Linfocitos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/microbiología , Inestabilidad de Microsatélites , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/microbiología , Escape del Tumor , Microambiente TumoralRESUMEN
Humans have coevolved with a complex community of bacterial species also referred to as the microbiome, which reciprocally provides critical contributions to human metabolism and immune system development. Gut microbiome composition differs significantly between individuals depending on host genetics, diet, and environmental factors. A dysregulation of the symbiotic nature of the intestinal host-microbial relationship and an aberrant and persistent immune response are the fundamental processes involved in inflammatory bowel diseases (IBD). Considering the essential role of T cells in IBD and the contributing role of the microbiome in shaping the immune response during the pathogenesis of IBD, this review focuses on the complex relationship, interplay, and communication between the gut microbiome and T cells, including their differentiation into different subsets of effector or regulatory cells.
Asunto(s)
Microbioma Gastrointestinal/inmunología , Tolerancia Inmunológica , Enfermedades Inflamatorias del Intestino/inmunología , Linfocitos T/inmunología , Humanos , Enfermedades Inflamatorias del Intestino/microbiología , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Simbiosis , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/microbiología , Linfocitos T/microbiología , Linfocitos T/patologíaRESUMEN
Lipoarabinomannan (LAM) is a major cell wall component of Mycobacterium tuberculosis (Mtb). LAM specific human T-lymphocytes release interferon-γ (IFNγ) and have antimicrobial activity against intracellular Mtb suggesting that they contribute to protection. Therefore the induction of LAM-specific memory T-cells is an attractive approach for the design of a new vaccine against tuberculosis. A prerequisite for the activation of LAM-specific T-cells is the efficient uptake and transport of the glycolipid antigen to the CD1 antigen presenting machinery. Based on the hydrophobicity of LAM we hypothesized that packaging of LAM into liposomes will support the activation of T-lymphocytes. We prepared liposomes containing phosphatidylcholine, cholesterol, stearylated octaarginine and LAM via thin layer hydration method (LIPLAM). Flow cytometry analysis using fluorescently labelled LIPLAM showed an efficient uptake by antigen presenting cells. LAM delivered via liposomes was biologically active as demonstrated by the down-regulation of peroxisome proliferator activated receptor gamma (PPARγ) protein expression. Importantly, LIPLAM induced higher IFNγ production by primary human T-lymphocytes than purified LAM (2-16 times) or empty liposomes. These results suggest that the delivery of mycobacterial glycolipids via liposomes is a promising approach to promote the induction of M. tuberculosis specific T-cell responses.