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1.
bioRxiv ; 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38585842

RESUMO

Tissue-resident memory CD8 T cells (TRM) kill infected cells and recruit additional immune cells to limit pathogen invasion at barrier sites. Small intestinal (SI) TRM cells consist of distinct subpopulations with higher expression of effector molecules or greater memory potential. We hypothesized that occupancy of diverse anatomical niches imprints these distinct TRM transcriptional programs. We leveraged human samples and a murine model of acute systemic viral infection to profile the location and transcriptome of pathogen-specific TRM cell differentiation at single-transcript resolution. We developed computational approaches to capture cellular locations along three anatomical axes of the small intestine and to visualize the spatiotemporal distribution of cell types and gene expression. TRM populations were spatially segregated: with more effector- and memory-like TRM preferentially localized at the villus tip or crypt, respectively. Modeling ligand-receptor activity revealed patterns of key cellular interactions and cytokine signaling pathways that initiate and maintain TRM differentiation and functional diversity, including different TGFß sources. Alterations in the cellular networks induced by loss of TGFßRII expression revealed a model consistent with TGFß promoting progressive TRM maturation towards the villus tip. Ultimately, we have developed a framework for the study of immune cell interactions with the spectrum of tissue cell types, revealing that T cell location and functional state are fundamentally intertwined.

2.
Cancer Immunol Res ; 11(12): 1571-1577, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37906619

RESUMO

The Arthur and Sandra Irving Cancer Immunology Symposium has been created as a platform for established cancer immunologists to mentor trainees and young investigators as they launch their research career in the field. By sharing their different paths to success, the senior faculty mentors provide an invaluable resource to support the development of the next generation of leaders in the cancer immunology community. This Commentary describes some of the key topics that were discussed during the 2022 symposium: scientific and career trajectory, leadership, mentoring, collaborations, and publishing. For each of these topics, established investigators discussed the elements that facilitate success in these areas as well as mistakes that can hinder progress. Herein, we outline the critical points raised in these discussions for establishing a successful independent research career. These points are highly relevant for the broader scientific community.


Assuntos
Tutoria , Neoplasias , Médicos , Humanos , Mentores , Pesquisadores , Neoplasias/terapia
3.
Nat Immunol ; 24(2): 267-279, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36543958

RESUMO

CD8+ T cells are critical for elimination of cancer cells. Factors within the tumor microenvironment (TME) can drive these cells to a hypofunctional state known as exhaustion. The most terminally exhausted T (tTex) cells are resistant to checkpoint blockade immunotherapy and might instead limit immunotherapeutic efficacy. Here we show that intratumoral CD8+ tTex cells possess transcriptional features of CD4+Foxp3+ regulatory T cells and are similarly capable of directly suppressing T cell proliferation ex vivo. tTex cell suppression requires CD39, which generates immunosuppressive adenosine. Restricted deletion of CD39 in endogenous CD8+ T cells resulted in slowed tumor progression, improved immunotherapy responsiveness and enhanced infiltration of transferred tumor-specific T cells. CD39 is induced on tTex cells by tumor hypoxia, thus mitigation of hypoxia limits tTex suppression. Together, these data suggest tTex cells are an important regulatory population in cancer and strategies to limit their generation, reprogram their immunosuppressive state or remove them from the TME might potentiate immunotherapy.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Humanos , Antígenos CD , Hipóxia , Neoplasias/terapia , Linfócitos T Reguladores , Microambiente Tumoral
4.
Sci Immunol ; 7(74): eabj9123, 2022 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-35930654

RESUMO

Response rates to immunotherapy in solid tumors remain low due in part to the elevated prevalence of terminally exhausted T cells, a hypofunctional differentiation state induced through persistent antigen and stress signaling. However, the mechanisms promoting progression to terminal exhaustion in the tumor remain undefined. Using the low-input chromatin immunoprecipitation sequencing method CUT&RUN, we profiled the histone modification landscape of tumor-infiltrating CD8+ T cells throughout differentiation. We found that terminally exhausted T cells had unexpected chromatin features that limit their transcriptional potential. Terminally exhausted T cells had a substantial fraction of active chromatin, including active enhancers enriched for bZIP/AP-1 transcription factor motifs that lacked correlated gene expression, which was restored by immunotherapeutic costimulatory signaling. Reduced transcriptional potential was also driven by an increase in histone bivalency, which we linked directly to hypoxia exposure. Enforced expression of the hypoxia-insensitive histone demethylase Kdm6b was sufficient to overcome hypoxia, increase function, and promote antitumor immunity. Our study reveals the specific epigenetic changes mediated by histone modifications during T cell differentiation that support exhaustion in cancer, highlighting that their altered function is driven by improper costimulatory signals and environmental factors. These data suggest that even terminally exhausted T cells may remain competent for transcription in settings of increased costimulatory signaling and reduced hypoxia.


Assuntos
Cromatina , Neoplasias , Linfócitos T CD8-Positivos , Cromatina/metabolismo , Histonas/metabolismo , Humanos , Hipóxia/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Microambiente Tumoral
5.
Eur J Immunol ; 51(9): 2225-2236, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34146342

RESUMO

Polymorphisms in TACI, a BAFF family cytokine receptor, are linked to diverse human immune disorders including common variable immunodeficiency (CVID) and systemic lupus erythematosus (SLE). Functional studies of individual variants show modest impacts on surface TACI expression and/or downstream signal transduction, indicating that relatively subtle variation in TACI activity can impact human B-cell biology. However, significant complexity underlies TACI biology, including both positive and negative regulation of physiologic and pathogenic B-cell responses. To model these contradictory events, we compared the functional impact of TACI deletion on separate models of murine SLE driven by T cell-independent and -dependent breaks in B-cell tolerance. First, we studied whether reduced surface TACI expression was sufficient to protect against progressive BAFF-mediated systemic autoimmunity. Strikingly, despite a relatively modest impact on surface TACI levels, TACI haploinsufficiency markedly reduced pathogenic RNA-associated autoantibody titers and conferred long-term protection from BAFF-driven lupus nephritis. In contrast, B cell-intrinsic TACI deletion exerted a limited impact of autoantibody generation in murine lupus characterized by spontaneous germinal center formation and T cell-dependent humoral autoimmunity. Together, these combined data provide new insights into TACI biology and highlight how TACI signals must be tightly regulated during protective and pathogenic B-cell responses.


Assuntos
Autoimunidade/genética , Fator Ativador de Células B/imunologia , Nefrite Lúpica/genética , Nefrite Lúpica/imunologia , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Autoimunidade/imunologia , Fator Ativador de Células B/antagonistas & inibidores , Fator Ativador de Células B/genética , Receptor do Fator Ativador de Células B/genética , Linfócitos B/imunologia , Quimera , Feminino , Haploinsuficiência/genética , Imunossupressores/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Proteína Transmembrana Ativadora e Interagente do CAML/imunologia
6.
J Exp Med ; 218(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34037670

RESUMO

In response to infection, pathogen-specific CD8 T cells differentiate into functionally diverse effector and memory T cell populations critical for resolving disease and providing durable immunity. Through small-molecule inhibition, RNAi studies, and induced genetic deletion, we reveal an essential role for the chromatin modifier and BET family member BRD4 in supporting the differentiation and maintenance of terminally fated effector CD8 T cells during infection. BRD4 bound diverse regulatory regions critical to effector T cell differentiation and controlled transcriptional activity of terminal effector-specific super-enhancers in vivo. Consequentially, induced deletion of Brd4 or small molecule-mediated BET inhibition impaired maintenance of a terminal effector T cell phenotype. BRD4 was also required for terminal differentiation of CD8 T cells in the tumor microenvironment in murine models, which we show has implications for immunotherapies. Taken together, these data reveal an unappreciated requirement for BRD4 in coordinating activity of cis regulatory elements to control CD8 T cell fate and lineage stability.


Assuntos
Linfócitos T CD8-Positivos/citologia , Diferenciação Celular/imunologia , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Viroses/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Cromatina/metabolismo , Elementos Facilitadores Genéticos/genética , Camundongos Knockout , Neoplasias/imunologia , Neoplasias/patologia , Proteínas Nucleares/deficiência , Ligação Proteica , Interferência de RNA , Fatores de Transcrição/deficiência , Transcrição Gênica
7.
Nat Rev Immunol ; 21(11): 718-738, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33981085

RESUMO

Cytotoxic CD8+ T cells play a key role in the elimination of intracellular infections and malignant cells and can provide long-term protective immunity. In the response to infection, CD8+ T cell metabolism is coupled to transcriptional, translational and epigenetic changes that are driven by extracellular metabolites and immunological signals. These programmes facilitate the adaptation of CD8+ T cells to the diverse and dynamic metabolic environments encountered in the circulation and in the tissues. In the setting of disease, both cell-intrinsic and cell-extrinsic metabolic cues contribute to CD8+ T cell dysfunction. In addition, changes in whole-body metabolism, whether through voluntary or disease-induced dietary alterations, can influence CD8+ T cell-mediated immunity. Defining the metabolic adaptations of CD8+ T cells in specific tissue environments informs our understanding of how these cells protect against pathogens and tumours and maintain tissue health at barrier sites. Here, we highlight recent findings revealing how metabolic networks enforce specific CD8+ T cell programmes and discuss how metabolism is integrated with CD8+ T cell differentiation and function and determined by environmental cues.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Infecções/metabolismo , Neoplasias/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Humanos , Infecções/imunologia , Ativação Linfocitária , Neoplasias/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo
8.
J Clin Invest ; 131(7)2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33792560

RESUMO

Adoptive T cell therapies (ACTs) hold great promise in cancer treatment, but low overall response rates in patients with solid tumors underscore remaining challenges in realizing the potential of this cellular immunotherapy approach. Promoting CD8+ T cell adaptation to tissue residency represents an underutilized but promising strategy to improve tumor-infiltrating lymphocyte (TIL) function. Here, we report that deletion of the HIF negative regulator von Hippel-Lindau (VHL) in CD8+ T cells induced HIF-1α/HIF-2α-dependent differentiation of tissue-resident memory-like (Trm-like) TILs in mouse models of malignancy. VHL-deficient TILs accumulated in tumors and exhibited a core Trm signature despite an exhaustion-associated phenotype, which led to retained polyfunctionality and response to αPD-1 immunotherapy, resulting in tumor eradication and protective tissue-resident memory. VHL deficiency similarly facilitated enhanced accumulation of chimeric antigen receptor (CAR) T cells with a Trm-like phenotype in tumors. Thus, HIF activity in CD8+ TILs promotes accumulation and antitumor activity, providing a new strategy to enhance the efficacy of ACTs.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Linfócitos T CD8-Positivos/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Imunidade Celular , Memória Imunológica , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Experimentais/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Tumoral , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Linfócitos do Interstício Tumoral/patologia , Camundongos , Camundongos Knockout , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/imunologia
9.
Nat Immunol ; 22(2): 205-215, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33398183

RESUMO

Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic and metabolic characteristics. However, drivers of exhaustion remain poorly understood. As intratumoral exhausted T cells experience severe hypoxia, we hypothesized that metabolic stress alters their responses to other signals, specifically, persistent antigenic stimulation. In vitro, although CD8+ T cells experiencing continuous stimulation or hypoxia alone differentiated into functional effectors, the combination rapidly drove T cell dysfunction consistent with exhaustion. Continuous stimulation promoted Blimp-1-mediated repression of PGC-1α-dependent mitochondrial reprogramming, rendering cells poorly responsive to hypoxia. Loss of mitochondrial function generated intolerable levels of reactive oxygen species (ROS), sufficient to promote exhausted-like states, in part through phosphatase inhibition and the consequent activity of nuclear factor of activated T cells. Reducing T cell-intrinsic ROS and lowering tumor hypoxia limited T cell exhaustion, synergizing with immunotherapy. Thus, immunologic and metabolic signaling are intrinsically linked: through mitigation of metabolic stress, T cell differentiation can be altered to promote more functional cellular fates.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Metabolismo Energético , Ativação Linfocitária , Linfócitos do Interstício Tumoral/metabolismo , Melanoma Experimental/metabolismo , Mitocôndrias/metabolismo , Microambiente Tumoral , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Feminino , Células HEK293 , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/imunologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Hipóxia Tumoral
10.
Cancer Immunol Res ; 7(8): 1258-1266, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31239318

RESUMO

Multiple studies have associated the transcription factor IRF1 with tumor-suppressive activities. Here, we report an opposite tumor cell-intrinsic function of IRF1 in promoting tumor growth. IRF1-deficient tumor cells showed reduced tumor growth in MC38 and CT26 colon carcinoma and B16 melanoma mouse models. This reduction in tumor growth was dependent on host CD8+ T cells. Detailed profiling of tumor-infiltrating leukocytes did not show changes in the various T-cell and myeloid cell populations. However, CD8+ T cells that had infiltrated IRF1-deficieint tumors in vivo exhibited enhanced cytotoxicity. IRF1-deficient tumor cells lost the ability to upregulate PD-L1 expression in vitro and in vivo and were more susceptible to T-cell-mediated killing. Induced expression of PD-L1 in IRF1-deficient tumor cells restored tumor growth. These results indicate differential activity of IRF1 in tumor escape.


Assuntos
Antígeno B7-H1/genética , Regulação Neoplásica da Expressão Gênica , Imunomodulação , Fator Regulador 1 de Interferon/metabolismo , Animais , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Humanos , Memória Imunológica , Imunomodulação/genética , Fator Regulador 1 de Interferon/genética , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Melanoma Experimental , Camundongos , Camundongos Knockout , Linfócitos T/imunologia , Linfócitos T/metabolismo
11.
J Exp Med ; 215(4): 1091-1100, 2018 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-29511066

RESUMO

Despite remarkable responses to cancer immunotherapy in a subset of patients, many patients remain resistant to these therapies. The tumor microenvironment can impose metabolic restrictions on T cell function, creating a resistance mechanism to immunotherapy. We have previously shown tumor-infiltrating T cells succumb to progressive loss of metabolic sufficiency, characterized by repression of mitochondrial activity that cannot be rescued by PD-1 blockade. 4-1BB, a costimulatory molecule highly expressed on exhausted T cells, has been shown to influence metabolic function. We hypothesized that 4-1BB signaling might provide metabolic support to tumor-infiltrating T cells. 4-1BB costimulation of CD8+ T cells results in enhanced mitochondrial capacity (suggestive of fusion) and engages PGC1α-mediated pathways via activation of p38-MAPK. 4-1BB treatment of mice improves metabolic sufficiency in endogenous and adoptive therapeutic CD8+ T cells. 4-1BB stimulation combined with PD-1 blockade results in robust antitumor immunity. Sequenced studies revealed the metabolic support afforded by 4-1BB agonism need not be continuous and that a short course of anti-4-1BB pretreatment was sufficient to provide a synergistic response. Our studies highlight metabolic reprogramming as the dominant effect of 4-1BB therapy and suggest that combinatorial strategies using 4-1BB agonism may help overcome the immunosuppressive metabolic landscape of the tumor microenvironment.


Assuntos
Imunoterapia , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Mitocôndrias/metabolismo , Biogênese de Organelas , Linfócitos T/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Animais , Anticorpos/farmacologia , Camundongos Endogâmicos C57BL , Dinâmica Mitocondrial , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/agonistas , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
Cell Rep ; 22(6): 1509-1521, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29425506

RESUMO

To fulfill bioenergetic demands of activation, T cells perform aerobic glycolysis, a process common to highly proliferative cells in which glucose is fermented into lactate rather than oxidized in mitochondria. However, the signaling events that initiate aerobic glycolysis in T cells remain unclear. We show T cell activation rapidly induces glycolysis independent of transcription, translation, CD28, and Akt and not involving increased glucose uptake or activity of glycolytic enzymes. Rather, TCR signaling promotes activation of pyruvate dehydrogenase kinase 1 (PDHK1), inhibiting mitochondrial import of pyruvate and facilitating breakdown into lactate. Inhibition of PDHK1 reveals this switch is required acutely for cytokine synthesis but dispensable for cytotoxicity. Functionally, cytokine synthesis is modulated via lactate dehydrogenase, which represses cytokine mRNA translation when aerobic glycolysis is disengaged. Our data provide mechanistic insight to metabolic contribution to effector T cell function and suggest that T cell function may be finely tuned through modulation of glycolytic activity.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Glicólise/imunologia , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia
13.
Cancer Immunol Res ; 5(1): 9-16, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27941003

RESUMO

Blockade of the coinhibitory checkpoint molecule PD-1 has emerged as an effective treatment for many cancers, resulting in remarkable responses. However, despite successes in the clinic, most patients do not respond to PD-1 blockade. Metabolic dysregulation is a common phenotype in cancer, but both patients and tumors are metabolically heterogeneous. We hypothesized that the deregulated oxidative energetics of tumor cells present a metabolic barrier to antitumor immunity through the generation of a hypoxic microenvironment and that normalization of tumor hypoxia might improve response to immunotherapy. We show that the murine tumor lines B16 and MC38 differed in their ability to consume oxygen and produce hypoxic environments, which correlated with their sensitivity to checkpoint blockade. Metformin, a broadly prescribed type II diabetes treatment, inhibited oxygen consumption in tumor cells in vitro and in vivo, resulting in reduced intratumoral hypoxia. Although metformin monotherapy had little therapeutic benefit in highly aggressive tumors, combination of metformin with PD-1 blockade resulted in improved intratumoral T-cell function and tumor clearance. Our data suggest tumor hypoxia acts as a barrier to immunotherapy and that remodeling the hypoxic tumor microenvironment has potential to convert patients resistant to immunotherapy into those that receive clinical benefit. Cancer Immunol Res; 5(1); 9-16. ©2016 AACR.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Metformina/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Hipóxia Tumoral/efeitos dos fármacos , Hipóxia Tumoral/imunologia , Animais , Citocinas/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Sinergismo Farmacológico , Metabolismo Energético/genética , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Melanoma Experimental , Camundongos , Consumo de Oxigênio/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral/imunologia
14.
Vaccines (Basel) ; 4(4)2016 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-27929420

RESUMO

When a T cell infiltrates a tumor, it is subjected to a variety of immunosuppressive and regulatory signals in the microenvironment. However, it is becoming increasingly clear that due to the proliferative and energetically-deregulated nature of tumor cells, T cells also operate at a metabolic disadvantage. The nutrient dearth of the tumor microenvironment (TME) creates "metabolic checkpoints" upon infiltrating T cells, impacting their ability to survive, proliferate and function effectively. In this review, we summarize the basics of tumor cell and T cell metabolism and discuss recent advances elucidating the individual metabolic checkpoints exerted on T cells that drive their dysfunction in the TME.

15.
J Immunol ; 197(12): 4529-4534, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27837104

RESUMO

Patients with systemic lupus erythematosus exhibit accelerated atherosclerosis, a chronic inflammatory disease of the arterial wall. The impact of B cells in atherosclerosis is controversial, with both protective and pathogenic roles described. For example, natural IgM binding conserved oxidized lipid epitopes protect against atherosclerosis, whereas anti-oxidized low-density lipoprotein (oxLDL) IgG likely promotes disease. Because BAFF promotes B cell class-switch recombination and humoral autoimmunity, we hypothesized that excess BAFF would accelerate atherosclerosis. In contrast, BAFF overexpression markedly reduced hypercholesterolemia and atherosclerosis in hyperlipidemic mice. BAFF-mediated atheroprotection required B cells and was associated with increased protective anti-oxLDL IgM. Surprisingly, high-titer anti-oxLDL IgM production and reduced atherosclerosis was dependent on the BAFF family receptor transmembrane activator and CAML interactor. In summary, we identified a novel role for B cell-specific, BAFF-dependent transmembrane activator and CAML interactor signals in atherosclerosis pathogenesis, of particular relevance to the use of BAFF-targeted therapies in systemic lupus erythematosus.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Aterosclerose/imunologia , Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismo , Animais , Autoanticorpos/sangue , Fator Ativador de Células B/genética , Células Cultivadas , Humanos , Switching de Imunoglobulina , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteína Transmembrana Ativadora e Interagente do CAML/genética
17.
Immunity ; 45(2): 374-88, 2016 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-27496732

RESUMO

Although tumor-specific T cells recognize cancer cells, they are often rendered dysfunctional due to an immunosuppressive microenvironment. Here we showed that T cells demonstrated persistent loss of mitochondrial function and mass when infiltrating murine and human tumors, an effect specific to the tumor microenvironment and not merely caused by activation. Tumor-infiltrating T cells showed a progressive loss of PPAR-gamma coactivator 1α (PGC1α), which programs mitochondrial biogenesis, induced by chronic Akt signaling in tumor-specific T cells. Reprogramming tumor-specific T cells through enforced expression of PGC1α resulted in superior intratumoral metabolic and effector function. Our data support a model in which signals in the tumor microenvironment repress T cell oxidative metabolism, resulting in effector cells with metabolic needs that cannot be met. Our studies also suggest that modulation or reprogramming of the altered metabolism of tumor-infiltrating T cells might represent a potential strategy to reinvigorate dysfunctional T cells for cancer treatment.


Assuntos
Neoplasias do Colo/imunologia , Linfócitos do Interstício Tumoral/imunologia , Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Reprogramação Celular , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias Experimentais , Proteína Oncogênica v-akt/metabolismo , Estresse Oxidativo , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Transdução de Sinais , Microambiente Tumoral
18.
J Exp Med ; 213(5): 733-50, 2016 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-27069113

RESUMO

Dysregulated germinal center (GC) responses are implicated in the pathogenesis of human autoimmune diseases, including systemic lupus erythematosus (SLE). Although both type 1 and type 2 interferons (IFNs) are involved in lupus pathogenesis, their respective impacts on the establishment of autoimmune GCs has not been addressed. In this study, using a chimeric model of B cell-driven autoimmunity, we demonstrate that B cell type 1 IFN receptor signals accelerate, but are not required for, lupus development. In contrast, B cells functioning as antigen-presenting cells initiate CD4(+) T cell activation and IFN-γ production, and strikingly, B cell-intrinsic deletion of the IFN-γ receptor (IFN-γR) abrogates autoimmune GCs, class-switched autoantibodies (auto-Abs), and systemic autoimmunity. Mechanistically, although IFN-γR signals increase B cell T-bet expression, B cell-intrinsic deletion of T-bet exerts an isolated impact on class-switch recombination to pathogenic auto-Ab subclasses without impacting GC development. Rather, in both mouse and human B cells, IFN-γ synergized with B cell receptor, toll-like receptor, and/or CD40 activation signals to promote cell-intrinsic expression of the GC master transcription factor, B cell lymphoma 6 protein. Our combined findings identify a novel B cell-intrinsic mechanism whereby IFN signals promote lupus pathogenesis, implicating this pathway as a potential therapeutic target in SLE.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Proteínas Proto-Oncogênicas c-bcl-6/imunologia , Receptores de Interferon/imunologia , Transdução de Sinais/imunologia , Animais , Autoanticorpos/imunologia , Linfócitos B/patologia , Centro Germinativo/patologia , Interferon gama/genética , Interferon gama/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Masculino , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-bcl-6/genética , Receptores de Interferon/genética , Transdução de Sinais/genética , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Receptor de Interferon gama
19.
J Immunol ; 196(9): 3525-31, 2016 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-27022196

RESUMO

Mice overexpressing B cell activating factor of the TNF family (BAFF) develop systemic autoimmunity characterized by class-switched anti-nuclear Abs. Transmembrane activator and CAML interactor (TACI) signals are critical for BAFF-mediated autoimmunity, but the B cell developmental subsets undergoing TACI-dependent activation in settings of excess BAFF remain unclear. We report that, although surface TACI expression is usually limited to mature B cells, excess BAFF promotes the expansion of TACI-expressing transitional B cells. TACI(+) transitional cells from BAFF-transgenic mice are characterized by an activated, cycling phenotype, and the TACI(+) cell subset is specifically enriched for autoreactivity, expresses activation-induced cytidine deaminase and T-bet, and exhibits evidence of somatic hypermutation. Consistent with a potential contribution to BAFF-mediated humoral autoimmunity, TACI(+) transitional B cells from BAFF-transgenic mice spontaneously produce class-switched autoantibodies ex vivo. These combined findings highlight a novel mechanism through which BAFF promotes humoral autoimmunity via direct, TACI-dependent activation of transitional B cells.


Assuntos
Autoanticorpos/biossíntese , Fator Ativador de Células B/metabolismo , Células Precursoras de Linfócitos B/imunologia , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismo , Animais , Autoanticorpos/imunologia , Autoimunidade , Fator Ativador de Células B/genética , Subpopulações de Linfócitos B/imunologia , Ativação Linfocitária , Camundongos , Camundongos Transgênicos , Células Precursoras de Linfócitos B/fisiologia , Proteína Transmembrana Ativadora e Interagente do CAML/genética
20.
Eur J Immunol ; 45(10): 2773-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26256668

RESUMO

Patients with Wiskott-Aldrich syndrome (WAS) exhibit prominent defects in splenic marginal zone (MZ), resulting in abnormal T-cell-independent antibody responses and increased bacterial infections. B-cell-intrinsic deletion of the affected gene WAS protein (WASp) markedly reduces splenic MZ B cells, without impacting the rate of MZ B-cell development, suggesting that abnormal B-cell retention within the MZ accounts for MZ defects in WAS. Since WASp regulates integrin-dependent actin cytoskeletal rearrangement, we previously hypothesized that defective B-cell integrin function promotes MZ depletion. In contrast, we now report that B-cell-intrinsic deletion of the TLR signaling adaptor MyD88 is sufficient to restore the MZ in WAS. We further identify TLR7, an endosomal single-stranded RNA (ssRNA) receptor, as the MyD88-dependent receptor responsible for WAS MZ depletion. These findings implicate spontaneous activation of MZ B cells by ssRNA-containing self-ligands (likely derived from circulating apoptotic material) as the mechanism underlying MZ depletion in WAS. Together, these data suggest a previously unappreciated role for B-cell intrinsic TLR signals in MZ homeostasis, of relevance to both pathogen responses and to the development of systemic autoimmunity.


Assuntos
Linfócitos B/imunologia , Glicoproteínas de Membrana/imunologia , Transdução de Sinais/imunologia , Baço/imunologia , Receptor 7 Toll-Like/imunologia , Síndrome de Wiskott-Aldrich/imunologia , Animais , Linfócitos B/patologia , Citoesqueleto/genética , Citoesqueleto/imunologia , Modelos Animais de Doenças , Integrinas/genética , Integrinas/imunologia , Depleção Linfocítica , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Transdução de Sinais/genética , Baço/patologia , Receptor 7 Toll-Like/genética , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/patologia
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