Spelling suggestions: "subject:"egulatory T cells"" "subject:"egulatory T wells""
41 |
Ex vivo imaging immune cell interactions in T cell vaccine-induced immunity and CD8+CD25+ T regulatory cell-mediated immune suppression2013 October 1900 (has links)
The ultimate goal of antitumor vaccines is to develop memory CD8+ cytotoxic T lymphocytes (CTLs), which are critical mediators of antitumor immunity. Previous work in our lab demonstrated that the ovalbumin (OVA)-specific CD4+ T cell-based (OVA-TEXO) vaccine generated using OVA-pulsed dendritic cell (DCOVA)-released exosomes (EXOOVA) stimulates CTL responses via interleukin (IL)-2 and costimulatory CD80 signaling. To assess the potential involvement of other costimulatory pathways and to define the key constituent of costimulation for memory CTL development, we first immunized wild-type (WT) C57BL/6 and gene-knockout mice with WT CD4+ OVA-TEXO cells or OVA-TEXO cells with various molecular deficiencies. We then assessed OVA-specific primary and recall CTL responses using PE-H-2Kb/OVA257–264 tetramer and FITC-anti-CD8 antibody staining by flow cytometry. We also examined antitumor immunity against the OVA-expressing B16 melanoma cell line BL6-10OVA. We demonstrate that CD4+ OVA-TEXO cells form immunological synapses with cognate CD8+ T cells in vitro. By assessment of the pattern of ex vivo interactions between OTI CD8+ T cells and OVA-TEXO or (Kb-/-)TEXO cells lacking peptide/major histocompatibitity complex (pMHC)-I expression, we provide the first visible evidence on the critical role of exosomal pMHC-I in targeting OVA-TEXO to cognate CD8+ T cells using two-photon microscopy. By assessing primary and recall CTL responses in mice immunized with OVA-TEXO cells or with OVA-TEXO cells lacking the costimulatory molecules CD40L, 4-1BBL or OX40L, we demonstrated that these costimulatory signals are dispensable for CTL priming by OVA-TEXO cells. Interestingly, CD40L, but not 4-1BBL or OX40L, plays a crucial role in the development of functional memory CTLs against BL6-10OVA tumors. Overall, this work suggests that a novel CD4+ T cell-based vaccine that is capable of stimulating long-term functional CTL memory via CD40L signaling may represent a novel, efficient approach to antitumor vaccination.
Breast cancer is the most common cancer among women in the western world. Approximately 20-30% of invasive breast carcinomas are proto-oncogene human epidermal growth factor receptor (HER)-2 positive and associated with increased metastatic potential and poor prognosis. The survival benefit of anti-HER2 driven therapies demonstrated in clinical trials indicates that HER2 is one of the most promising molecules for targeted therapy to date. Above results prompt us to assess whether CD4+ T-cell-based vaccine can stimulate efficient HER2-specific CD8+ CTL responses and antitumor immunity in transgenic mice with HER2-specific self-immune tolerance. We prepared HER2-specific HER2-TEXO using ConA-stimulated CD4+ T cells with uptake of exosomes released from HER2-expressing AdVHER2-transfected DCs. We found that HER2-TEXO vaccine is capable of inducing HER2-specific CTL responses and protective immunity against transgene HLA-A2/HER2-expressing B16 melanoma BL6-10HLA-A2/HER2 in 2/8 double transgenic HLA-A2/HER2 mice with HER2-specific self-immune tolerance. The remaining 6/8 mice had significantly prolonged survival. Therefore, the novel T cell-based HER2-TEXO vaccine may provide a new therapeutic alternative for women with HER2+ breast cancer.
In contrast to CD4+CD25+ regulatory T cells (Tregs), mechanisms of CD8+CD25+ Treg-mediated immunosuppression are not well understood. In this study, we purified polyclonal CD8+CD25+ Tregs from C57BL/6 mouse splenocytes and expanded them in culture medium containing CD3/CD28 microbeads. By using these amplified CD8+CD25+ Tregs, we demonstrated that CD8+CD25+ Tregs inhibit naive CD4+ T-cell proliferation and induce naive T-cell anergy by up-regulating T-cell anergy-associated early growth response 2 (EGR2), and by decreasing T-cell proliferation and IL-2-secretion upon stimulation. They also impact the expression of perforin on effector CTLs and directly induce perforin-mediated CTL apoptosis. CD8+CD25+ Tregs, when pulsed with OVA323-339 peptide, exert an enhanced inhibition. Interestingly, CD8+CD25+ Tregs, when pulsed with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide, become capable of inhibiting MOG35-55-induced experimental autoimmune encephalomyelitis (EAE). Two-photon microscopic observations suggest that OVA323-339-pulsed (armed) CD8+CD25+ Tregs reduce the interactions between DCs and cognate CD4+ T cells ex vivo by increasing velocities of T cells in mouse lymph nodes. Therefore, redirecting antigen-specificity to nonspecific CD8+CD25+ Tregs can be achieved for enhanced immunosuppression through their arming with the antigen-specific pMHC-II complexes. This approach may have great impact on improvement of endogenous polyclonal Treg-mediated immunotherapy for autoimmune diseases.
Taken together, our studies demonstrate that nonspecific polyclonal CD4+ T cells and CD8+CD25+ Tregs, when armed with HER2 and MOG antigen-specific pMHC-I and -II complexes, become capable of stimulating enhanced HER2-specific CTL responses and antitumor immunity in double transgenic HLA-A2/HER2 mice and inducing enhanced MOG-specific immunosuppression in MOG-induced EAE mice, respectively. Therefore, redirecting antigen specificity to nonspecific CD4+ T and CD8+CD25+ Tregs by pMHC complex arming may have great impact in development of novel T cell-based vaccines for treatment of cancer and autoimmune diseases.
|
42 |
The effects of topical calcipotriol treatment on immune responses to vaccinationBach, Paxton John 11 1900 (has links)
1,25-dihydroxyvitamin D3 (Vitamin D) is a potent immunomodulator capable of generating regulatory T cells (Tregs) and contributing to immune tolerance. Additionally, vitamin D has been shown to promote mucosal immunity when used as a vaccine adjuvant. We show here that pretreatment of an area of skin with the synthetic vitamin D analog calcipotriol combined with transcutaneous immunization results in the induction of CD4⁺CD25⁺ Tregs capable of inhibiting the elicitation of a contact hypersensitivity response. We also demonstrate that topical calcipotriol has significant effects on the immune response to subcutaneously injected vaccines, and compare it with another common topical immunosuppressant, the corticosteroid betamethasone-17-valerate (BMV). Functionally, calcipotriol and BMV treatment both result in the suppression of CD8⁺ T cell priming in response to subcutaneous vaccination, despite the topical co-administration of the potent Th1 inducing TLR9 agonist unmethylated CpG DNA. The effects of calcipotriol on the humoral response are subtler as we observe marginally increased production of antigen-specific IgG1 immunoglobulins along with a strong suppression of the IgG2a isotype. This is in contrast to pretreatment with BMV, which instead suppresses the production of IgG1 and IgA antibodies. In the draining lymph nodes of calcipotriol treated animals, we see no change in the percentage of Foxp3⁺ CD4⁺ T cells post-immunization, but show that tolerance is transferable with the adoptive transfer of CD4⁺CD25⁺ cells. Despite a decrease in the percentage of antigen-bearing APCs in the DLN of calcipotriol treated animals, the DCs maintain high expression of co-stimulatory markers and can induce CD4⁺ T cell proliferation ex vivo. Our data indicate that calcipotriol has distinct effects on immune responses to subcutaneous vaccines consistent with its role as an immunomodulator, although the mechanism(s) through which it is acting remain unclear. We believe that further research is warranted into its potential use as part of a treatment modality for allergy and autoimmune disorders.
|
43 |
Defining the biological role of FOXP3 in human CD4+ T cellsAllan, Sarah E. 11 1900 (has links)
The involvement of regulatory T cells (Tregs) in immune homeostasis is now recognized as one of the fundamental mechanisms of immune tolerance. While several different types of Tregs cooperate to establish and maintain immune homeostasis, much current research is focused on defining the characteristics of the CD4⁺CD25⁺ Treg subset, as these cells can mediate dominant, long-lasting and transferable tolerance in many experimental models.
The aim of this research was to characterize the biological role of a protein known as forkhead box P3 (FOXP3) that was initially identified as an essential transcription factor for the development of mouse CD4⁺CD25⁺ Tregs, in human CD4⁺ T cells. Following confirmation that, like mouse Tregs, human Tregs also expressed high levels of FOXP3, several approaches were used to investigate the role of this protein in human CD4⁺ T cells. 1) Characterization of endogenous FOXP3 expression in CD4⁺ T cell subsets revealed that this protein is not a Treg-specific marker as was previously thought. Instead, low-level and transient expression was found to be typical of highly activated non-regulatory effector T cells. 2) To generate large numbers of Tregs suitable for cellular therapy, the capacity of ectopic FOXP3 expression to drive Treg generation in vitro was explored. It was found that high and constitutive expression mediated by a lentiviral vector, but not fluctuating expression driven by a retroviral vector, was sufficient to generate suppressive cells. Over-expression strategies were also used to characterize a novel splice isoform unique to human cells, FOXP3Δ2 (FOXP3b). 3) To further probe the requirements of FOXP3 to induce suppressor function, a system for conditionally-active FOXP3 ectopic expression was developed. These studies established that FOXP3 acts a quantitative regulator rather than a “master switch” for Tregs, and that there is a temporal component to its capacity to direct Treg phenotype and function.
In summary, this research has significantly expanded the understanding of the biological function of FOXP3 in human CD4⁺ T cells. Based on the potential of these cells to be manipulated for therapy, this work contributes to the field of immunology on both academic and clinical research fronts.
|
44 |
Effective Combination of Syngeneic HCT with CRCL Vaccination to Treat BCR-ABL+ Leukemia and CD4+CD25+FoxP3+ Regulatory T Cells Suppress Mycobacterium Tuberculosis Immunity in Patients with Active DiseaseChen, Xinchun January 2006 (has links)
Chronic myelogenous leukemia (CML) is a clonal hematopoetic stem cell disorder characterized by proliferation of cells expressing BCR-ABL fusion protein. In the BCR-ABL+ leukemia murine model, 12B1, we explored the therapeutic applicability of chaperone-rich cell lysate (CRCL) in the context of syngeneic hematopoietic cell transplantation (HCT) to treat pre-existing leukemia. Our results demonstrate that tumor growth is significantly delayed in mice receiving syngeneic HCT from 12B1 tumor CRCL immunized donors compared to animals receiving HCT from non-immunized donors. CRCL immunization post-immune HCT further hindered tumor growth when compared to immune HCT without post-transplant vaccination. The magnitude of the immune response was consistent with the anti-tumor effects observed in vivo. We also demonstrated that cured mice had developed long-term tumor specific immunity against 12B1 tumor cells. In addition, we documented that both T cells and NK cells contributed to the anti-tumor effect of CRCL vaccination as depletion of either subset hampered tumor growth delay. Thus, our results suggest that CRCL represents a promising vaccine capable of generating specific immune responses. This anti-tumor immunity can be effectively transferred to a host via HCT and further enhanced post-HCT with additional tumor CRCL immunizations.CD4+CD25+ regulatory T cells (Treg) play a central role in the prevention of autoimmunity and in the control of immune responses by down-regulating the function of effector CD4+ or CD8+ T cells. The role of Treg in Mycobacterium tuberculosis infection and persistence is inadequately documented. Therefore, the current study was designed to determine whether CD4+CD25+ FoxP3+ regulatory T cells may modulate immunity against human tuberculosis (TB). Ourresults indicate that the number of CD4+CD25+FoxP3+ Treg increases in the blood or at the site of infection in active TB patients. The frequency of CD4+CD25+FoxP3+ Treg in pleural fluid inversely correlates with local MTB-specific immunity(p<0.002). These CD4+CD25+FoxP3+ T lymphocytes isolated from the blood and pleural fluid are capable of suppressing MTB-specific IFN-γ and IL-10 production in TB patients. Therefore, CD4+CD25+FoxP3+ Treg expanded in TB patients suppress Mycobacterium tuberculosis immunity and may therefore contribute to the pathogenesis of human TB.
|
45 |
Defining the biological role of FOXP3 in human CD4+ T cellsAllan, Sarah E. 11 1900 (has links)
The involvement of regulatory T cells (Tregs) in immune homeostasis is now recognized as one of the fundamental mechanisms of immune tolerance. While several different types of Tregs cooperate to establish and maintain immune homeostasis, much current research is focused on defining the characteristics of the CD4⁺CD25⁺ Treg subset, as these cells can mediate dominant, long-lasting and transferable tolerance in many experimental models.
The aim of this research was to characterize the biological role of a protein known as forkhead box P3 (FOXP3) that was initially identified as an essential transcription factor for the development of mouse CD4⁺CD25⁺ Tregs, in human CD4⁺ T cells. Following confirmation that, like mouse Tregs, human Tregs also expressed high levels of FOXP3, several approaches were used to investigate the role of this protein in human CD4⁺ T cells. 1) Characterization of endogenous FOXP3 expression in CD4⁺ T cell subsets revealed that this protein is not a Treg-specific marker as was previously thought. Instead, low-level and transient expression was found to be typical of highly activated non-regulatory effector T cells. 2) To generate large numbers of Tregs suitable for cellular therapy, the capacity of ectopic FOXP3 expression to drive Treg generation in vitro was explored. It was found that high and constitutive expression mediated by a lentiviral vector, but not fluctuating expression driven by a retroviral vector, was sufficient to generate suppressive cells. Over-expression strategies were also used to characterize a novel splice isoform unique to human cells, FOXP3Δ2 (FOXP3b). 3) To further probe the requirements of FOXP3 to induce suppressor function, a system for conditionally-active FOXP3 ectopic expression was developed. These studies established that FOXP3 acts a quantitative regulator rather than a “master switch” for Tregs, and that there is a temporal component to its capacity to direct Treg phenotype and function.
In summary, this research has significantly expanded the understanding of the biological function of FOXP3 in human CD4⁺ T cells. Based on the potential of these cells to be manipulated for therapy, this work contributes to the field of immunology on both academic and clinical research fronts.
|
46 |
The effects of topical calcipotriol treatment on immune responses to vaccinationBach, Paxton John 11 1900 (has links)
1,25-dihydroxyvitamin D3 (Vitamin D) is a potent immunomodulator capable of generating regulatory T cells (Tregs) and contributing to immune tolerance. Additionally, vitamin D has been shown to promote mucosal immunity when used as a vaccine adjuvant. We show here that pretreatment of an area of skin with the synthetic vitamin D analog calcipotriol combined with transcutaneous immunization results in the induction of CD4⁺CD25⁺ Tregs capable of inhibiting the elicitation of a contact hypersensitivity response. We also demonstrate that topical calcipotriol has significant effects on the immune response to subcutaneously injected vaccines, and compare it with another common topical immunosuppressant, the corticosteroid betamethasone-17-valerate (BMV). Functionally, calcipotriol and BMV treatment both result in the suppression of CD8⁺ T cell priming in response to subcutaneous vaccination, despite the topical co-administration of the potent Th1 inducing TLR9 agonist unmethylated CpG DNA. The effects of calcipotriol on the humoral response are subtler as we observe marginally increased production of antigen-specific IgG1 immunoglobulins along with a strong suppression of the IgG2a isotype. This is in contrast to pretreatment with BMV, which instead suppresses the production of IgG1 and IgA antibodies. In the draining lymph nodes of calcipotriol treated animals, we see no change in the percentage of Foxp3⁺ CD4⁺ T cells post-immunization, but show that tolerance is transferable with the adoptive transfer of CD4⁺CD25⁺ cells. Despite a decrease in the percentage of antigen-bearing APCs in the DLN of calcipotriol treated animals, the DCs maintain high expression of co-stimulatory markers and can induce CD4⁺ T cell proliferation ex vivo. Our data indicate that calcipotriol has distinct effects on immune responses to subcutaneous vaccines consistent with its role as an immunomodulator, although the mechanism(s) through which it is acting remain unclear. We believe that further research is warranted into its potential use as part of a treatment modality for allergy and autoimmune disorders.
|
47 |
The role of interleukin 33 in intestinal homeostasisChomka, Agnieszka January 2016 (has links)
IL-33 is a pleiotropic cytokine that orchestrates both innate and adaptive immunity. It is commonly associated with type 2 immune responses but recently expression of the IL-33 receptor, ST2, was reported on Treg cells found preferentially in non-lymphoid tissues, such as the visceral adipose tissue, muscle or colon. A crucial role of Tregs in maintaining intestinal homeostasis has been well described. However, little is known about the functional relevance of the ST2-expressing Treg population in the colon. Phenotypic and functional characterisation of Tregs in the gut revealed the presence of two distinct populations: ST2<sup>+</sup>/Gata3<sup>+</sup> and Rorγt<sup>+</sup> Tregs. Thymic-derived ST2<sup>+</sup>/Gata3<sup>+</sup> Tregs showed a more activated phenotype and produced IL-10 under homeostatic conditions. Upon microbial challenge and colitis, ST2+/Gata3+ Tregs were decreased, while Rorγt<sup>+</sup> Tregs expanded. Furthermore, in vitro experiments demonstrated that IL-33 directly induced activation of the Gata3 pathway in Tregs, which enhanced expression of Foxp3 and ST2. Additionally, amphiregulin was also induced in Tregs upon stimulation with IL-33. However, in vivo, IL-33 was dispensable for both the maintenance of Treg cells under homeostatic conditions and Treg function in Helicobacter hepaticus-driven colitis. Investigation of the negative regulators of IL-33 showed that IL-23 inhibited IL-33-mediated effects on Tregs. We also observed increased production of soluble ST2 by stromal cells during intestinal inflammation, which likely contributed to the reduction of IL-33 bioavailability. Finally, a systematic analysis of the cellular source of IL-33 revealed that PDGRFα<sup>+</sup> stromal cells located in the T cell zone of secondary and tertiary lymphoid tissues were a major IL-33-producing cell population in the gut. Collectively, our findings suggest that signals received by the stromal compartment upon cell injury may trigger a specific phenotype of Tregs with a repair capacity, and thus, promote intestinal homeostasis. These findings improve our understanding of tissue-resident Tregs and open an exciting avenue to explore heterocellular signalling between stromal cells and Tregs.
|
48 |
Exercise in haemodialysis patients : impact on markers of inflammationDungey, Maurice January 2015 (has links)
End-stage renal disease patients have a greatly increased risk of cardiovascular disease partly attributed to the elevated levels of systemic inflammation observed in uraemia. One of the key mechanisms underlying inflammation appears to be the immune dysfunction that afflicts almost every aspect of the uraemic immune system. As a consequence patients experience immunosuppression and reduced responsiveness to antigen as well as a simultaneous over-activation leading to a pro-inflammatory environment. In addition, the haemodialysis (HD) treatment itself induces a proinflammatory response but may provide an otherwise opportune time to complete supervised exercise.
|
49 |
Participação das células T de memória e linfócitos CD4.CD25+Foxp3 (reguladores) nos mecanismos de resistência à infecção experimental pelo trypanosoma cruziNihei, Jorge Sadao January 2013 (has links)
Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2013-10-11T17:20:48Z
No. of bitstreams: 1
Jorge Sadao Nihei.pdf: 1524347 bytes, checksum: eb6417af423845038169df9f7824ead9 (MD5) / Made available in DSpace on 2013-10-11T17:20:48Z (GMT). No. of bitstreams: 1
Jorge Sadao Nihei.pdf: 1524347 bytes, checksum: eb6417af423845038169df9f7824ead9 (MD5)
Previous issue date: 2013 / Universidade Federal da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / A infecção pelo Trypanosoma cruzi (T. cruzi) resulta em uma resposta imune que controla a predominância do parasito, mas é incapaz de eliminá-lo completamente, levando a persistência do parasito. A gravidade da doença de Chagas está correlacionada com a persistência do parasito nos tecidos musculares, neurais e intestinais. A função imunorregulatória das células T reguladoras em limitar a resposta imune poderia ser explorada no sentido de erificar a sua quantidade e qualidade no modelo experimental de infecção por T. cruzi. O principal objetivo deste projeto foi estudar a participação e influência dos linfócitos Treg sobre os mecanismos de resistência a infecção por T. cruzi, principalmente sobre a geração/manutenção de células T CD4+ e CD8+ memória efetora e central. Para tal, foi realizado um estudo comparativo da importância dos linfócitos T, e alterações das células Treg na infecção experimental por T. cruzi, de animais susceptíveis (C57Bl/6) e resistentes (BALB/c) nos dias 10, 20 e 30 apos a infecção. Adicionalmente, com o objetivo de investigar o papel das células T reguladoras, foi realizada a neutralização da citocina IL-2, com o tratamento in vivo com anti-IL-2 monoclonal (clone JES6-1A12), em animais C57Bl/6, durante a infecção com a cepa Tulahuen de T. cruzi. A análise da cinética de infecção (10, 20 e 30 dias) revelou que os animais resistentes (BALB/c) apresentaram maior expansão de células T efetoras CD4+ e CD8+ no baço e no tecido muscular esquelético. Os dados coletados demonstram que o tratamento com anti-IL-2 resultou em diminuição significativa da população de células T CD4+CD25+Foxp3+ nos animais infectados, comparado ao grupo infectado e tratado com imunoglobulina de rato. A diminuição das células Treg nestes animais resultou em alterações importantes nos mecanismos efetores como, por exemplo: o aumento da expansão das células T CD4+ e CD8+ efetoras e a produção de citocinas pró-inflamatórias e anti-inflamatórias no baço e tecido muscular esquelético. O reflexo destas alterações foi relacionado à diminuição da parasitemia e da mortalidade dos animais. Desta forma, as células Treg parecem exercer um controle da resposta imune efetora ao T. cruzi no sentido de tentar controlar a disseminação do patógeno e, ao mesmo tempo, impedir a destruição tecidual decorrente de uma exacerbação da resposta imune. Portanto, sugere-se que as células Treg estariam participando da resposta imune ao T. cruzi no sentido de modular a resposta imune efetora. / The Trypanosoma cruzi (T. cruzi) infection results in an immune response that controls the
parasite prevalence, but is unable to eliminate it completely, leading to infection persistence. The
severity of Chagas’ disease is correlated with the parasite persistence in the muscle, neural and
bowel tissues. The immunorregulatory function of regulatory T cells in limiting the immune
response could be exploited in order to verify its quantity and functional activities in an
experimental model of T. cruzi infection. The main objective of this project was to study the
participation and influence of Treg lymphocytes on the mechanisms of resistance to T. cruzi
infection, mainly on generation and maintenance of central/effector memory T cells. In the first
step, it was conducted a comparative study of the importance of T lymphocytes and alterations
of Treg cells in experimental T. cruzi infection in susceptible (C57BL/6) and resistant (BALB/c)
animals for 10, 20 and 30 days of infection. Additionally, in order to investigate the role of
regulatory T cells, it was performed the neutralization of the cytokine IL-2, with the in vivo
treatment with anti-IL-2 monoclonal antibody (clone JES6-1A12) of C57Bl/6 animals during
infection with Tulahuen strain of T. cruzi. The analysis of the kinetics of infection (10, 20 and 30
days) revealed that the resistant animals (BALB/c) showed greater expansion and effector
activity of the CD4+ and CD8+ splenic T cells and skeletal muscle tissue. The collected data
demonstrate that the treatment with anti-IL-2 resulted in significant reduction of
CD4+CD25+Foxp3+ T cells population in infected animals, compared to those infected and
untreated. The decrease of Treg cells in those animals resulted in significant changes in the
effector mechanisms such as: an increase in expansion of CD4+ and CD8+ T effector cells, and
production of pro-inflammatory and anti-inflammatory cytokines in the spleen and skeletal
muscle tissue. The reflection of these changes was verified by the decrease in parasitemia and
mortality of the animals. Thus, Treg cells seem to have control of the effector immune response
to T. cruzi in trying to control the spread of the pathogen and, at the same time, preventing
tissue destruction due to an exacerbation of the immune response. Therefore, it is suggested
that Treg cells would be participating in the immune response to T. cruzi by modulating the
effector immune response.
|
50 |
Células T reguladoras representam um fator de susceptibilidade na tuberculose experimental / Regulatory T Cells may represent a susceptibiliy factor in experimental tuberculosisMarina Oliveira e Paula 06 January 2009 (has links)
Dentre as infecções bacterianas, a tuberculose é responsável pelo maior número de casos no mundo. É uma doença freqüentemente fatal quando associada com cepas resistentes e extremamente resistentes às drogas, ao abandono de tratamento e imunossupressão. Dependendo da natureza e da magnitude da resposta do hospedeiro, uma inflamação excessiva, comumente não protetora nos indivíduos susceptíveis, acompanha a progressão da infecção. Nesse sentido, é de grande interesse identificar mecanismos que não somente caracterizem a evolução da infecção como também aqueles que participam no controle do dano tecidual. Neste estudo, nós usamos linhagens de animais com susceptibilidade distinta à infecção por M. tuberculosis com o objetivo de avaliar se a freqüência e a atividade das células T reguladoras são influenciadas por características genéticas do hospedeiro e se essas diferenças poderiam representar um fator de susceptibilidade durante a tuberculose experimental. Nossos resultados mostram que tanto a freqüência como a atividade supressora das células T reguladoras de animais BALB/c estava aumentada, inibindo a produção de IFN-g e IL-2 por células efetoras CD4+CD25-. Essa atividade supressora não parece ser dependente de IL-10 ou TGF-b. Do contrário, a freqüência e a capacidade supressoras das células T reguladoras de animais C57BL/6 diminuíram com a infecção e, como conseqüência, foi verificada uma resposta proliferativa mais intensa, maior produção de IFN-g e IL-17, e uma eficiente restrição no crescimento bacteriano em relação aos animais BALB/c. As células T reguladoras de animais C57BL/6 regularam positivamente a produção de TGF-b. No entanto, não regularam negativamente a produção de IFN-g. Além disso, a transferência adotiva de células T reguladoras de animais BALB/c tornou esta linhagem mais susceptível enquanto a transferência de células T reguladoras de animais C57BL/6 afetou discretamente o número de UFC nessa linhagem. Reforçando nossos dados, recentemente, foi descrito por Torcia e colaboradores (2008) que a deficiência funcional de células T reguladoras pode explicar a resistência distinta à malária em diferentes grupos étnicos da África. Nesse contexto, a ativação de células T reguladoras pode representar um importante aspecto a ser ressaltado no desenvolvimento de medidas profiláticas e de terapias imunológicas para doenças infecciosas em indivíduos susceptíveis. / Tuberculosis is responsible for the highest number of cases of bacterial infection in the world, which are frequently fatal, especially when associated with multiply drug-resistant and extremely resistant strains, treatment abandonment and immune suppression. Depending on the nature and magnitude of the host response, an excessive inflammation follows the progression of infection. In this way, it is of great interest to identify mechanisms that not only determine differences in infection outcome, but also those that are most influential in controlling host tissue damage. In this study, we used mouse strains with distinct levels of susceptibility to M. tuberculosis infection to test the hypothesis that the frequency and activity of Treg cells are influenced by genetic background and these differences might represent a susceptibility factor for tuberculosis. Our results show that either the frequency or the suppressor activity of BALB/c Treg cells was enhanced, inhibiting proliferation, IFN-g and IL-2 production by CD4+CD25- responsive cells. This suppressor activity seems not be dependent on IL-10 or TGF-b. In contrast, the frequency and suppressor capacity of C57BL/6 Treg cells decreased and, as a consequence, a more intense proliferative response, higher production of IFN-g and IL-17, and a more efficient restriction of bacterial growth compared to BALB/c mice were observed. C57BL/6 regulatory T cells up regulated TGF-b secretion. However, they did not down regulated IFN-g secretion. In addition, adoptive transfer of BALB/c Treg cells made this strain more susceptible to infection while the transfer of C57BL/6 Treg cells affected only discretely the CFU numbers in this strain. To reinforce our data, recently, it was reported by Torcia and coworkers that a functional deficiency of regulatory T cells may explain distinct resistance to malaria in different ethnic groups of Africa. In this context, activation of Treg cells may become an important issue to be addressed in the development of vaccines and immune modulators for the prophylaxis and therapy of infectious diseases in susceptible subjects.
|
Page generated in 0.0616 seconds