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1.
Cell Rep ; 30(4): 1039-1051.e5, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31995748

RESUMO

Interleukin-35 (IL-35) is an immunosuppressive cytokine composed of Epstein-Barr-virus-induced protein 3 (Ebi3) and IL-12α chain (p35) subunits, yet the forms that IL-35 assume and its role in peripheral tolerance remain elusive. We induce CBA-specific, IL-35-producing T regulatory (Treg) cells in TregEbi3WT C57BL/6 reporter mice and identify IL-35 producers by expression of Ebi3TdTom gene reporter plus Ebi3 and p35 proteins. Curiously, both subunits of IL-35 are displayed on the surface of tolerogen-specific Foxp3+ and Foxp3neg (iTr35) T cells. Furthermore, IL-35 producers, although rare, secrete Ebi3 and p35 on extracellular vesicles (EVs) targeting a 25- to 100-fold higher number of T and B lymphocytes, causing them to acquire surface IL-35. This surface IL-35 is absent when EV production is inhibited or if Ebi3 is genetically deleted in Treg cells. The unique ability of EVs to coat bystander lymphocytes with IL-35, promoting exhaustion in, and secondary suppression by, non-Treg cells identifies a novel mechanism of infectious tolerance.

2.
Semin Immunol ; 42: 101305, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31604537

RESUMO

Immune checkpoint therapy has revolutionized cancer treatment by blocking inhibitory pathways in T cells that limits the an effective anti-tumor immune response. Therapeutics targeting CTLA-4 and PD1/PDL1 have progressed to first line therapy in multiple tumor types with some patients exhibiting tumor regression or remission. However, the majority of patients do not benefit from checkpoint therapy emphasizing the need for alternative therapeutic options. Lymphocyte Activation Gene 3 (LAG3) or CD223 is expressed on multiple cell types including CD4+ and CD8+ T cells, and Tregs, and is required for optimal T cell regulation and homeostasis. Persistent antigen-stimulation in cancer or chronic infection leads to chronic LAG3 expression, promoting T cell exhaustion. Targeting LAG3 along with PD1 facilitates T cell reinvigoration. A substantial amount of pre-clinical data and mechanistic analysis has led to LAG3 being the third checkpoint to be targeted in the clinic with nearly a dozen therapeutics under investigation. In this review, we will discuss the structure, function and role of LAG3 in murine and human models of disease, including autoimmune and inflammatory diseases, chronic viral and parasitic infections, and cancer, emphasizing new advances in the development of LAG3-targeting immunotherapies for cancer that are currently in clinical trials.

3.
Immunity ; 51(2): 381-397.e6, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31350177

RESUMO

Regulatory T (Treg) cells are crucial for immune homeostasis, but they also contribute to tumor immune evasion by promoting a suppressive tumor microenvironment (TME). Mice with Treg cell-restricted Neuropilin-1 deficiency show tumor resistance while maintaining peripheral immune homeostasis, thereby providing a controlled system to interrogate the impact of intratumoral Treg cells on the TME. Using this and other genetic models, we showed that Treg cells shaped the transcriptional landscape across multiple tumor-infiltrating immune cell types. Treg cells suppressed CD8+ T cell secretion of interferon-γ (IFNγ), which would otherwise block the activation of sterol regulatory element-binding protein 1 (SREBP1)-mediated fatty acid synthesis in immunosuppressive (M2-like) tumor-associated macrophages (TAMs). Thus, Treg cells indirectly but selectively sustained M2-like TAM metabolic fitness, mitochondrial integrity, and survival. SREBP1 inhibition augmented the efficacy of immune checkpoint blockade, suggesting that targeting Treg cells or their modulation of lipid metabolism in M2-like TAMs could improve cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Macrófagos/metabolismo , Melanoma/imunologia , Neoplasias Experimentais/imunologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Carcinogênese , Diferenciação Celular , Ácidos Graxos/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Evasão da Resposta Imune , Interferon gama/metabolismo , Macrófagos/imunologia , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuropilina-1/genética , Células Th2/imunologia , Microambiente Tumoral
4.
Immunology ; 157(3): 232-247, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31087644

RESUMO

Regulatory T (Treg) cells play a crucial role in maintaining self-tolerance and resolution of immune responses by employing multifaceted immunoregulatory mechanisms. However, Treg cells readily infiltrate into the tumor microenvironment (TME) and dampen anti-tumor immune responses, thereby becoming a barrier to effective cancer immunotherapy. There has been a substantial expansion in the development of novel immunotherapies targeting various inhibitory receptors (IRs), such as CTLA4, PD1 and LAG3, but these approaches have mechanistically focused on the elicitation of anti-tumor responses. However, enhanced inflammation in the TME could also play a detrimental role by facilitating the recruitment, stability and function of Treg cells by up-regulating chemokines that promote Treg cell migration, and/or increasing inhibitory cytokine production. Furthermore, IR blockade may enhance Treg cell function and survival, thereby serving as a resistance mechanism against effective immunotherapy. Given that Treg cells are comprised of functionally and phenotypically heterogeneous sub-populations that may alter their characteristics in a context-dependent manner, it is critical to identify unique molecular pathways that are preferentially used by intratumoral Treg cells. In this review, we discuss markers that serve to identify certain Treg cell subsets, distinguished by chemokine receptors, IRs and cytokines that facilitate their migration, stability and function in the TME. We also discuss how these Treg cell subsets correlate with the clinical outcome of patients with various types of cancer and how they may serve as potential TME-specific targets for novel cancer immunotherapies.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Evasão Tumoral , Animais , Quimiocinas/imunologia , Quimiocinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Fenótipo , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Microambiente Tumoral
5.
Nat Immunol ; 20(6): 724-735, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30936494

RESUMO

Regulatory T cells (Treg cells) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. Treg cells subvert beneficial anti-tumor immunity by modulating inhibitory receptor expression on tumor-infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms have remained elusive. Here, we found that the cytokines IL-10 and IL-35 (Ebi3-IL-12α heterodimer) were divergently expressed by Treg cell subpopulations in the tumor microenvironment (TME) and cooperatively promoted intratumoral T cell exhaustion by modulating several inhibitory receptor expression and exhaustion-associated transcriptomic signature of CD8+ TILs. While expression of BLIMP1 (encoded by Prdm1) was a common target, IL-10 and IL-35 differentially affected effector T cell versus memory T cell fates, respectively, highlighting their differential, partially overlapping but non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated cooperative roles for Treg cell-derived IL-10 and IL-35 in promoting BLIMP1-dependent exhaustion of CD8+ TILs that limits effective anti-tumor immunity.


Assuntos
Imunidade Celular , Interleucina-10/metabolismo , Interleucinas/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Transferência Adotiva , Animais , Citocinas/genética , Citocinas/metabolismo , Perfilação da Expressão Gênica , Humanos , Melanoma Experimental , Camundongos , Neoplasias/patologia , Transdução de Sinais , Transcriptoma
6.
Sci Immunol ; 2(9)2017 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-28783703

RESUMO

Inhibitory receptors (IRs) are pivotal in controlling T cell homeostasis because of their intrinsic regulation of conventional effector T (Tconv) cell proliferation, viability, and function. However, the role of IRs on regulatory T cells (Tregs) remains obscure because they could be required for suppressive activity and/or limit Treg function. We evaluated the role of lymphocyte activation gene 3 (LAG3; CD223) on Tregs by generating mice in which LAG3 is absent on the cell surface of Tregs in a murine model of type 1 diabetes. Unexpectedly, mice that lacked LAG3 expression on Tregs exhibited reduced autoimmune diabetes, consistent with enhanced Treg proliferation and function. Whereas the transcriptional landscape of peripheral wild-type (WT) and Lag3-deficient Tregs was largely comparable, substantial differences between intra-islet Tregs were evident and involved a subset of genes and pathways that promote Treg maintenance and function. Consistent with these observations, Lag3-deficient Tregs outcompeted WT Tregs in the islets but not in the periphery in cotransfer experiments because of enhanced interleukin-2-signal transducer and activator of transcription 5 signaling and increased Eos expression. Our study suggests that LAG3 intrinsically limits Treg proliferation and function at inflammatory sites, promotes autoimmunity in a chronic autoimmune-prone environment, and may contribute to Treg insufficiency in autoimmune disease.

7.
Cell ; 169(6): 1130-1141.e11, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28552348

RESUMO

Regulatory T cells (Tregs) are a barrier to anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral Treg stability and function but is dispensable for peripheral immune tolerance. Treg-restricted Nrp1 deletion results in profound tumor resistance due to Treg functional fragility. Thus, identifying the basis for Nrp1 dependency and the key drivers of Treg fragility could help to improve immunotherapy for human cancer. We show that a high percentage of intratumoral NRP1+ Tregs correlates with poor prognosis in melanoma and head and neck squamous cell carcinoma. Using a mouse model of melanoma where Nrp1-deficient (Nrp1-/-) and wild-type (Nrp1+/+) Tregs can be assessed in a competitive environment, we find that a high proportion of intratumoral Nrp1-/- Tregs produce interferon-γ (IFNγ), which drives the fragility of surrounding wild-type Tregs, boosts anti-tumor immunity, and facilitates tumor clearance. We also show that IFNγ-induced Treg fragility is required for response to anti-PD1, suggesting that cancer therapies promoting Treg fragility may be efficacious.


Assuntos
Carcinoma de Células Escamosas/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Interferon gama/imunologia , Melanoma/imunologia , Linfócitos T Reguladores/imunologia , Animais , Feminino , Fatores de Transcrição Forkhead , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , Melanoma Experimental/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Neuropilina-1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Microambiente Tumoral
8.
Science ; 353(6307)2016 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-27708076

RESUMO

Emerging evidence indicates that the pathogenesis of Parkinson's disease (PD) may be due to cell-to-cell transmission of misfolded preformed fibrils (PFF) of α-synuclein (α-syn). The mechanism by which α-syn PFF spreads from neuron to neuron is not known. Here, we show that LAG3 (lymphocyte-activation gene 3) binds α-syn PFF with high affinity (dissociation constant = 77 nanomolar), whereas the α-syn monomer exhibited minimal binding. α-Syn-biotin PFF binding to LAG3 initiated α-syn PFF endocytosis, transmission, and toxicity. Lack of LAG3 substantially delayed α-syn PFF-induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo. The identification of LAG3 as a receptor that binds α-syn PFF provides a target for developing therapeutics designed to slow the progression of PD and related α-synucleinopathies.


Assuntos
Antígenos CD/metabolismo , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Animais , Neurônios Dopaminérgicos/metabolismo , Endocitose , Humanos , Camundongos , Camundongos Transgênicos , Ligação Proteica , Transporte Proteico , alfa-Sinucleína/genética
9.
Transplant Direct ; 2(5): e73, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27500263

RESUMO

BACKGROUND: The influence of donor-side regulation toward recipient antigens on graft outcome is poorly understood. METHODS: Because this influence might be due in part to the accumulation of tissue-resident memory T cells in the donor organ, we used a standard murine tolerization model (donor-specific transfusion plus CD40L blockade) to determine the kinetics of development and peripheralization of allospecific regulatory T cell in lymphoid tissues and liver, a secondary lymphoid organ used in transplantation. RESULTS: We found that donor-specific transfusion and CD40L blockade leads to a progressive and sustained T regulatory allospecific response. The cytokines IL10, TGFß, and IL35 all contributed to the regulatory phenomenon as determined by trans vivo delayed hypersensitivity assay. Unexpectedly, an early and transient self-specific regulatory response was found as well. Using double reporter mice (forkhead box p 3 [Foxp3]-yellow fluorescent protein, Epstein-Barr virus-induced gene 3 [Ebi3]-TdTomRed), we found an increase in Foxp3+CD25+ regulatory T (Treg) cells paralleling the regulatory response. The Ebi3+ CD4 T cells (IL35-producing) were mainly classic Treg cells (Foxp3+CD25+), whereas TGFß+ CD4 T cells are mostly Foxp3-negative, suggesting 2 different CD4 Treg cell subsets. Liver-resident TGFß+ CD4 T cells appeared more rapidly than Ebi3-producing T cells, whereas at later timepoints, the Ebi3 response predominated both in lymphoid tissues and liver. CONCLUSIONS: The timing of appearance of donor organ resident Treg cell subsets should be considered in experiments testing the role of bidirectional regulation in transplant tolerance.

10.
Immunity ; 44(2): 316-29, 2016 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-26872697

RESUMO

Regulatory T (Treg) cells pose a major barrier to effective anti-tumor immunity. Although Treg cell depletion enhances tumor rejection, the ensuing autoimmune sequelae limits its utility in the clinic and highlights the need for limiting Treg cell activity within the tumor microenvironment. Interleukin-35 (IL-35) is a Treg cell-secreted cytokine that inhibits T cell proliferation and function. Using an IL-35 reporter mouse, we observed substantial enrichment of IL-35(+) Treg cells in tumors. Neutralization with an IL-35-specific antibody or Treg cell-restricted deletion of IL-35 production limited tumor growth in multiple murine models of human cancer. Limiting intratumoral IL-35 enhanced T cell proliferation, effector function, antigen-specific responses, and long-term T cell memory. Treg cell-derived IL-35 promoted the expression of multiple inhibitory receptors (PD1, TIM3, LAG3), thereby facilitating intratumoral T cell exhaustion. These findings reveal previously unappreciated roles for IL-35 in limiting anti-tumor immunity and contributing to T cell dysfunction in the tumor microenvironment.


Assuntos
Anticorpos Bloqueadores/administração & dosagem , Interleucinas/metabolismo , Melanoma Experimental/imunologia , Neoplasias Cutâneas/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Receptor Celular 2 do Vírus da Hepatite A , Humanos , Memória Imunológica , Interleucinas/genética , Interleucinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Receptores Virais/genética , Receptores Virais/metabolismo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Microambiente Tumoral
11.
FEBS J ; 283(14): 2731-48, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26787424

RESUMO

Regulatory T (Treg ) cells play a crucial role in maintaining peripheral tolerance and preventing autoimmunity. However, they also represent a major barrier to effective antitumor immunity and immunotherapy. Consequently, there has been considerable interest in developing approaches that can selectively or preferentially target Treg cells in tumors, while not impacting their capacity to maintain peripheral immune homeostasis. In this review, we describe our current understanding of the mechanisms underlying the recruitment, expansion, and suppressive activity of tumor-associated Treg cells, and discuss the approaches used and the challenges encountered in the immunotherapeutic targeting of Treg cells. In addition, we summarize the primary clinical targets and some emerging data on exciting new potential Treg cell-restricted targets. We propose that discovering and understanding mechanisms that are preferentially used by Treg cells within the tumor microenvironment will lead to strategies that selectively target Treg cell-mediated suppression of antitumor immunity while maintaining peripheral immune tolerance.


Assuntos
Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T Reguladores/imunologia , Animais , Antineoplásicos/farmacologia , Membrana Celular/imunologia , Citocinas/biossíntese , Citotoxicidade Imunológica , Humanos , Imunoterapia , Depleção Linfocítica , Linfócitos do Interstício Tumoral/imunologia , Modelos Imunológicos , Tolerância Periférica , Linfócitos T Reguladores/efeitos dos fármacos , Microambiente Tumoral/imunologia
12.
J Biol Chem ; 290(32): 19796-805, 2015 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-26109064

RESUMO

The T cell receptor (TCR)-CD3 complex is composed of a genetically diverse αß TCR heterodimer associated noncovalently with the invariant CD3 dimers CD3ϵγ, CD3ϵδ, and CD3ζζ. The TCR mediates peptide-MHC recognition, whereas the CD3 molecules transduce activation signals to the T cell. Although much is known about downstream T cell signaling pathways, the mechanism whereby TCR engagement by peptide-MHC initiates signaling is poorly understood. A key to solving this problem is defining the spatial organization of the TCR-CD3 complex and the interactions between its subunits. We have applied solution NMR methods to identify the docking site for CD3 on the ß chain of a human autoimmune TCR. We demonstrate a low affinity but highly specific interaction between the extracellular domains of CD3 and the TCR constant ß (Cß) domain that requires both CD3ϵγ and CD3ϵδ subunits. The mainly hydrophilic docking site, comprising 9-11 solvent-accessible Cß residues, is relatively small (∼400 Å(2)), consistent with the weak interaction between TCR and CD3 extracellular domains, and devoid of glycosylation sites. The docking site is centered on the αA and αB helices of Cß, which are located at the base of the TCR. This positions CD3ϵγ and CD3ϵδ between the TCR and the T cell membrane, permitting us to distinguish among several possible models of TCR-CD3 association. We further correlate structural results from NMR with mutational data on TCR-CD3 interactions from cell-based assays.


Assuntos
Complexo CD3/química , Subunidades Proteicas/química , Complexo Receptor-CD3 de Antígeno de Linfócitos T/química , Receptores de Antígenos de Linfócitos T alfa-beta/química , Sequência de Aminoácidos , Complexo CD3/genética , Complexo CD3/imunologia , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Humanos , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , Dados de Sequência Molecular , Mutação , Dobramento de Proteína , Multimerização Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Subunidades Proteicas/genética , Subunidades Proteicas/imunologia , Complexo Receptor-CD3 de Antígeno de Linfócitos T/genética , Complexo Receptor-CD3 de Antígeno de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Linfócitos T/química , Linfócitos T/imunologia
13.
PLoS One ; 9(8): e104484, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25122007

RESUMO

Environmental factors including drugs, mineral oils and heavy metals such as lead, gold and mercury are triggers of autoimmune diseases in animal models or even in occupationally exposed humans. After exposure to subtoxic levels of mercury (Hg), genetically susceptible strains of mice develop an autoimmune disease characterized by the production of highly specific anti-nucleolar autoantibodies, hyperglobulinemia and nephritis. However, mice can be tolerized to the disease by a single low dose administration of Hg. Lymphocyte Activation Gene-3 (LAG-3) is a CD4-related, MHC-class II binding molecule expressed on activated T cells and NK cells which maintains lymphocyte homeostatic balance via various inhibitory mechanisms. In our model, administration of anti-LAG-3 monoclonal antibody broke tolerance to Hg resulting in autoantibody production and an increase in serum IgE level. In addition, LAG-3-deficient B6.SJL mice not only had increased susceptibility to Hg-induced autoimmunity but were also unresponsive to tolerance induction. Conversely, adoptive transfer of wild-type CD4(+) T cells was able to partially rescue LAG-3-deficient mice from the autoimmune disease. Further, in LAG-3-deficient mice, mercury elicited higher amounts of IL-6, IL-4 and IFN-γ, cytokines known to play a critical role in mercury-induced autoimmunity. Therefore, we conclude that LAG-3 exerts an important regulatory effect on autoimmunity elicited by a common environmental pollutant.


Assuntos
Antígenos CD/imunologia , Autoimunidade/imunologia , Poluentes Ambientais/imunologia , Ativação Linfocitária/imunologia , Animais , Anticorpos Antinucleares/imunologia , Autoanticorpos/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Tolerância Imunológica/imunologia , Imunoglobulina E/imunologia , Interferon gama/imunologia , Interleucina-4/imunologia , Interleucina-6/imunologia , Células Matadoras Naturais/imunologia , Mercúrio/efeitos adversos , Mercúrio/imunologia , Camundongos , Exposição Ocupacional
14.
Nature ; 501(7466): 252-6, 2013 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-23913274

RESUMO

Regulatory T cells (Treg cells) have a crucial role in the immune system by preventing autoimmunity, limiting immunopathology, and maintaining immune homeostasis. However, they also represent a major barrier to effective anti-tumour immunity and sterilizing immunity to chronic viral infections. The transcription factor Foxp3 has a major role in the development and programming of Treg cells. The relative stability of Treg cells at inflammatory disease sites has been a highly contentious subject. There is considerable interest in identifying pathways that control the stability of Treg cells as many immune-mediated diseases are characterized by either exacerbated or limited Treg-cell function. Here we show that the immune-cell-expressed ligand semaphorin-4a (Sema4a) and the Treg-cell-expressed receptor neuropilin-1 (Nrp1) interact both in vitro, to potentiate Treg-cell function and survival, and in vivo, at inflammatory sites. Using mice with a Treg-cell-restricted deletion of Nrp1, we show that Nrp1 is dispensable for suppression of autoimmunity and maintenance of immune homeostasis, but is required by Treg cells to limit anti-tumour immune responses and to cure established inflammatory colitis. Sema4a ligation of Nrp1 restrained Akt phosphorylation cellularly and at the immunologic synapse by phosphatase and tensin homologue (PTEN), which increased nuclear localization of the transcription factor Foxo3a. The Nrp1-induced transcriptome promoted Treg-cell stability by enhancing quiescence and survival factors while inhibiting programs that promote differentiation. Importantly, this Nrp1-dependent molecular program is evident in intra-tumoral Treg cells. Our data support a model in which Treg-cell stability can be subverted in certain inflammatory sites, but is maintained by a Sema4a-Nrp1 axis, highlighting this pathway as a potential therapeutic target that could limit Treg-cell-mediated tumour-induced tolerance without inducing autoimmunity.


Assuntos
Neuropilina-1/metabolismo , Semaforinas/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Autoimunidade/imunologia , Sobrevivência Celular , Colite/imunologia , Feminino , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/metabolismo , Células HEK293 , Homeostase/imunologia , Humanos , Tolerância Imunológica/imunologia , Sinapses Imunológicas , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Neuropilina-1/deficiência , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/citologia , Serina-Treonina Quinases TOR/metabolismo
16.
Diabetes ; 61(7): 1760-8, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22586584

RESUMO

Preventing activation of diabetogenic T cells is critical for delaying type 1 diabetes onset. The inhibitory molecule lymphocyte activation gene 3 (LAG-3) and metalloprotease tumor necrosis factor-α converting enzyme (TACE) work together to regulate TH1 responses. The aim of this study was to determine if regulating redox using a catalytic antioxidant (CA) could modulate TACE-mediated LAG-3 shedding to impede diabetogenic T-cell activation and progression to disease. A combination of in vitro experiments and in vivo analyses using NOD mouse strains was conducted to test the effect of redox modulation on LAG-3 shedding, TACE enzymatic function, and disease onset. Systemic treatment of NOD mice significantly delayed type 1 diabetes onset. Disease prevention correlated with decreased activation, proliferation, and effector function of diabetogenic T cells; reduced insulin-specific T-cell frequency; and enhanced LAG-3(+) cells. Redox modulation also affected TACE activation, diminishing LAG-3 cleavage. Furthermore, disease progression was monitored by measuring serum soluble LAG-3, which decreased in CA-treated mice. Therefore, affecting redox balance by CA treatment reduces the activation of diabetogenic T cells and impedes type 1 diabetes onset via decreasing T-cell effector function and LAG-3 cleavage. Moreover, soluble LAG-3 can serve as an early T-cell-specific biomarker for type 1 diabetes onset and immunomodulation.


Assuntos
Antígenos CD/metabolismo , Manganês/farmacologia , Metaloporfirinas/farmacologia , Superóxido Dismutase/farmacologia , Células Th1/efeitos dos fármacos , Proteínas ADAM/metabolismo , Proteína ADAM17 , Animais , Antígenos CD/sangue , Biomarcadores/sangue , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/prevenção & controle , Feminino , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos NOD , Oxirredução , Células Th1/metabolismo
17.
Cancer Res ; 72(4): 917-27, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22186141

RESUMO

Inhibitory receptors on immune cells are pivotal regulators of immune escape in cancer. Among these inhibitory receptors, CTLA-4 (targeted clinically by ipilimumab) serves as a dominant off-switch while other receptors such as PD-1 and LAG-3 seem to serve more subtle rheostat functions. However, the extent of synergy and cooperative interactions between inhibitory pathways in cancer remain largely unexplored. Here, we reveal extensive coexpression of PD-1 and LAG-3 on tumor-infiltrating CD4(+) and CD8(+) T cells in three distinct transplantable tumors. Dual anti-LAG-3/anti-PD-1 antibody treatment cured most mice of established tumors that were largely resistant to single antibody treatment. Despite minimal immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in multiple organs, leading to eventual lethality. However, Lag3(-/-)Pdcd1(-/-) mice showed markedly increased survival from and clearance of multiple transplantable tumors. Together, these results define a strong synergy between the PD-1 and LAG-3 inhibitory pathways in tolerance to both self and tumor antigens. In addition, they argue strongly that dual blockade of these molecules represents a promising combinatorial strategy for cancer.


Assuntos
Antígenos CD/fisiologia , Linfócitos T CD4-Positivos/imunologia , Neoplasias Experimentais/imunologia , Receptor de Morte Celular Programada 1/fisiologia , Evasão Tumoral/imunologia , Animais , Anticorpos/uso terapêutico , Antígenos CD/imunologia , Linhagem Celular Tumoral , Sinergismo Farmacológico , Tolerância Imunológica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Receptor de Morte Celular Programada 1/imunologia
18.
J Immunol ; 186(12): 6661-6, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21576509

RESUMO

Human regulatory T cells (T(reg)) are essential for the maintenance of immune tolerance. However, the mechanisms they use to mediate suppression remain controversial. Although IL-35 has been shown to play an important role in T(reg)-mediated suppression in mice, recent studies have questioned its relevance in human T(reg). In this study, we show that human T(reg) express and require IL-35 for maximal suppressive capacity. Substantial upregulation of EBI3 and IL12A, but not IL10 and TGFB, was observed in activated human T(reg) compared with conventional T cells (T(conv)). Contact-independent T(reg)-mediated suppression was IL-35 dependent and did not require IL-10 or TGF-ß. Lastly, human T(reg)-mediated suppression led to the conversion of the suppressed T(conv) into iTr35 cells, an IL-35-induced T(reg) population, in an IL-35-dependent manner. Thus, IL-35 contributes to human T(reg)-mediated suppression, and its conversion of suppressed target T(conv) into IL-35-induced T(reg) may contribute to infectious tolerance.


Assuntos
Tolerância Imunológica/imunologia , Interleucinas/imunologia , Linfócitos T Reguladores/imunologia , Humanos , Interleucina-10 , Subunidade p35 da Interleucina-12 , Antígenos de Histocompatibilidade Menor , Fator de Crescimento Transformador beta
19.
Blood ; 117(20): 5532-40, 2011 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-21422469

RESUMO

Administration of a single dose of anti-CD40L mAb at the time of allogeneic BM transplantation tolerizes peripheral alloreactive T cells and permits establishment of mixed hematopoietic chimerism in mice. Once engrafted, mixed chimeras are systemically tolerant to donor Ags through a central deletion mechanism and will accept any donor organ indefinitely. We previously found that the PD-1/PD-L1 pathway is required for CD8 T-cell tolerance in this model. However, the cell population that must express PD-1 and the role of other inhibitory molecules were unknown. Here, we report that LAG-3 is required for long-term peripheral CD8 but not CD4 T-cell tolerance and that this requirement is CD8 cell-extrinsic. In contrast, adoptive transfer studies revealed a CD8 T cell-intrinsic requirement for CTLA4/B7.1/B7.2 and for PD-1 for CD8 T-cell tolerance induction. We also observed that both PD-L1 and PD-L2 are independently required on donor cells to achieve T-cell tolerance. Finally, we uncovered a requirement for TGF-ß signaling into T cells to achieve peripheral CD8 but not CD4 T-cell tolerance in this in vivo system.


Assuntos
Antígenos CD/imunologia , Antígenos de Superfície/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Linfócitos T CD8-Positivos/imunologia , Tolerância Imunológica , Fator de Crescimento Transformador beta/imunologia , Transferência Adotiva , Animais , Antígenos CD/genética , Antígenos de Superfície/genética , Proteínas Reguladoras de Apoptose/deficiência , Proteínas Reguladoras de Apoptose/genética , Antígeno B7-1/genética , Antígeno B7-1/imunologia , Antígeno B7-H1 , Transplante de Medula Óssea/imunologia , Linfócitos T CD4-Positivos/imunologia , Ligante de CD40/antagonistas & inibidores , Antígeno CTLA-4 , Feminino , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Modelos Imunológicos , Peptídeos/deficiência , Peptídeos/genética , Peptídeos/imunologia , Proteína 2 Ligante de Morte Celular Programada 1 , Receptor de Morte Celular Programada 1 , Transdução de Sinais/imunologia , Transplante Homólogo
20.
Methods Mol Biol ; 707: 119-56, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21287333

RESUMO

To fully examine the functionality of a regulatory T cell (T(reg)) population, one needs to assess their ability to suppress in a variety of in vivo models. We describe five in vivo models that examine the suppressive capacity of T(regs) upon different target cell types. The advantages and disadvantages of each model including resources, time, and technical expertise required to execute each model are also described.


Assuntos
Modelos Animais de Doenças , Linfócitos T Reguladores/imunologia , Animais , Fatores de Transcrição Forkhead/genética , Genes RAG-1 , Camundongos
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