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1.
Cell Rep Med ; 4(1): 100878, 2023 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-36599350

RESUMO

Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming therapeutic resistance remains a critical challenge. Here we identify interleukin 6 (IL-6) as a correlate of poor response to atezolizumab (anti-PD-L1) in large clinical trials of advanced kidney, breast, and bladder cancers. In pre-clinical models, combined blockade of PD-L1 and the IL-6 receptor (IL6R) causes synergistic regression of large established tumors and substantially improves anti-tumor CD8+ cytotoxic T lymphocyte (CTL) responses compared with anti-PD-L1 alone. Circulating CTLs from cancer patients with high plasma IL-6 display a repressed functional profile based on single-cell RNA sequencing, and IL-6-STAT3 signaling inhibits classical cytotoxic differentiation of CTLs in vitro. In tumor-bearing mice, CTL-specific IL6R deficiency is sufficient to improve anti-PD-L1 activity. Thus, based on both clinical and experimental evidence, agents targeting IL-6 signaling are plausible partners for combination with ICIs in cancer patients.


Assuntos
Antineoplásicos , Interleucina-6 , Neoplasias , Animais , Camundongos , Antineoplásicos/uso terapêutico , Antígeno B7-H1/imunologia , Antígeno B7-H1/uso terapêutico , Linfócitos T CD8-Positivos/metabolismo , Imunoterapia , Interleucina-6/metabolismo , Neoplasias/imunologia , Neoplasias/terapia
2.
Sci Transl Med ; 14(627): eabf8188, 2022 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-35020406

RESUMO

Exacerbations of symptoms represent an unmet need for people with asthma. Bacterial dysbiosis and opportunistic bacterial infections have been observed in, and may contribute to, more severe asthma. However, the molecular mechanisms driving these exacerbations remain unclear. We show here that bacterial lipopolysaccharide (LPS) induces oncostatin M (OSM) and that airway biopsies from patients with severe asthma present with an OSM-driven transcriptional profile. This profile correlates with activation of inflammatory and mucus-producing pathways. Using primary human lung tissue or human epithelial and mesenchymal cells, we demonstrate that OSM is necessary and sufficient to drive pathophysiological features observed in severe asthma after exposure to LPS or Klebsiella pneumoniae. These findings were further supported through blockade of OSM with an OSM-specific antibody. Single-cell RNA sequencing from human lung biopsies identified macrophages as a source of OSM. Additional studies using Osm-deficient murine macrophages demonstrated that macrophage-derived OSM translates LPS signals into asthma-associated pathologies. Together, these data provide rationale for inhibiting OSM to prevent bacterial-associated progression and exacerbation of severe asthma.


Assuntos
Asma , Oncostatina M/metabolismo , Animais , Asma/patologia , Humanos , Pulmão/patologia , Macrófagos/metabolismo , Camundongos , Muco , Oncostatina M/genética
3.
J Immunol ; 199(1): 27-32, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28550204

RESUMO

In NOD mice, CD11c+ cells increase greatly with islet inflammation and contribute to autoimmune destruction of pancreatic ß cells. In this study, we investigated their origin and mechanism of recruitment. CD11c+ cells in inflamed islets resembled classical dendritic cells based on their transcriptional profile. However, the majority of these cells were not from the Zbtb46-dependent dendritic-cell lineage. Instead, monocyte precursors could give rise to CD11c+ cells in inflamed islets. Chemokines Ccl5 and Ccl8 were persistently elevated in inflamed islets and the influx of CD11c+ cells was partially dependent on their receptor Ccr5. Treatment with islet Ag-specific regulatory T cells led to a marked decrease of Ccl5 and Ccl8, and a reduction of monocyte recruitment. These results implicate a monocytic origin of CD11c+ cells in inflamed islets and suggest that therapeutic regulatory T cells directly or indirectly regulate their influx by altering the chemotactic milieu in the islets.


Assuntos
Antígeno CD11c/imunologia , Células Dendríticas/imunologia , Diabetes Mellitus Tipo 1/imunologia , Ilhotas Pancreáticas/imunologia , Monócitos/imunologia , Animais , Autoimunidade , Antígeno CD11c/genética , Antígeno CD11c/metabolismo , Movimento Celular , Quimiocina CCL5/genética , Quimiocina CCL5/imunologia , Quimiocina CCL8/genética , Quimiocina CCL8/imunologia , Feminino , Ilhotas Pancreáticas/patologia , Camundongos , Camundongos Endogâmicos NOD , Monócitos/fisiologia , Linfócitos T Reguladores/imunologia
4.
Curr Opin Immunol ; 37: 11-20, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26432763

RESUMO

Regulatory T (Treg) cells are crucial players in the prevention of autoimmunity. Treg lineage commitment and functional stability are influenced by selected extracellular signals from the local environment, shaped by distinctive intracellular signaling network, and secured by their unique epigenetic profile. Recent advances in our understanding of the complex processes of Treg lineage differentiation, maintenance, and function has paved the way for developing strategies to manipulate these important cells for therapeutic benefit in many diseases. In this review, we will summarize recent advances in our understanding of Treg biology as well as Treg-targeted therapies in the context of autoimmune disease.


Assuntos
Doenças Autoimunes/terapia , Imunoterapia , Linfócitos T Reguladores/imunologia , Animais , Doenças Autoimunes/imunologia , Diferenciação Celular , Microambiente Celular , Epigênese Genética , Humanos , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos
5.
J Immunol ; 194(7): 3147-55, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25732730

RESUMO

Therapeutic regulatory T cells (Tregs) can reverse pre-established autoimmune pathology. In this study, using a mouse model of autoimmune diabetes, we aimed to determine the means by which therapeutic Tregs control islet inflammation. Islet Ag-specific Tregs infiltrated inflamed islets soon after infusion into prediabetic mice, which was quickly followed by a selective reduction of mRNA associated with effector T cells in the islets. This change was partially due to decreased CD8(+) T cell accumulation in the tissue. CD8(+) T cells that remained in the islets after Treg treatment were able to engage dendritic cells in a manner similar to that found in untreated mice, consistent with the retention of an activated phenotype by islet dendritic cells shortly after Treg treatment. Nonetheless, Treg treatment abrogated IFN-γ production by intraislet CD8(+) and CD4(+) T cells at the protein level with minimal effect on IFN-γ mRNA. Sustained expression of IFN-γ protein by effector T cells was dependent on common γ-chain cytokine activation of the mTOR pathway, which was suppressed in islet CD8(+) T cells in vivo after Treg treatment. These multifaceted mechanisms underlie the efficacy of therapeutic Treg subversion of effector T cell functions at the site of inflammation to restore normal tissue homeostasis.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Movimento Celular/genética , Movimento Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/terapia , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Imunoterapia Adotiva , Interferon gama , Depleção Linfocítica , Camundongos , Camundongos Transgênicos , Transdução de Sinais , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Serina-Treonina Quinases TOR/metabolismo
6.
PLoS Pathog ; 9(10): e1003675, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24098124

RESUMO

Chronic intestinal parasite infection is a major global health problem, but mechanisms that promote chronicity are poorly understood. Here we describe a novel cellular and molecular pathway involved in the development of chronic intestinal parasite infection. We show that, early during development of chronic infection with the murine intestinal parasite Trichuris muris, TGFß signalling in CD4+ T-cells is induced and that antibody-mediated inhibition of TGFß function results in protection from infection. Mechanistically, we find that enhanced TGFß signalling in CD4+ T-cells during infection involves expression of the TGFß-activating integrin αvß8 by dendritic cells (DCs), which we have previously shown is highly expressed by a subset of DCs in the intestine. Importantly, mice lacking integrin αvß8 on DCs were completely resistant to chronic infection with T. muris, indicating an important functional role for integrin αvß8-mediated TGFß activation in promoting chronic infection. Protection from infection was dependent on CD4+ T-cells, but appeared independent of Foxp3+ Tregs. Instead, mice lacking integrin αvß8 expression on DCs displayed an early increase in production of the protective type 2 cytokine IL-13 by CD4+ T-cells, and inhibition of this increase by crossing mice to IL-4 knockout mice restored parasite infection. Our results therefore provide novel insights into how type 2 immunity is controlled in the intestine, and may help contribute to development of new therapies aimed at promoting expulsion of gut helminths.


Assuntos
Células Dendríticas/imunologia , Integrinas/imunologia , Enteropatias Parasitárias/imunologia , Células Th2/imunologia , Fator de Crescimento Transformador beta/imunologia , Tricuríase/imunologia , Trichuris/imunologia , Animais , Doença Crônica , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Integrinas/genética , Integrinas/metabolismo , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-13/metabolismo , Enteropatias Parasitárias/genética , Enteropatias Parasitárias/patologia , Camundongos , Camundongos Knockout , Células Th2/metabolismo , Células Th2/patologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Tricuríase/genética , Tricuríase/metabolismo , Tricuríase/patologia , Trichuris/genética , Trichuris/metabolismo
7.
Semin Immunopathol ; 34(6): 815-28, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23053395

RESUMO

Infection with soil-transmitted gastrointestinal parasites, such as Trichuris trichiura, affects more than a billion people worldwide, causing significant morbidity and health problems especially in poverty-stricken developing countries. Despite extensive research, the role of the immune system in triggering parasite expulsion is incompletely understood which hinders the development of anti-parasite therapies. Trichuris muris infection in mice serves as a useful model of T. trichiura infection in humans and has proven to be an invaluable tool in increasing our understanding of the role of the immune system in promoting either susceptibility or resistance to infection. The old paradigm of a susceptibility-associated Th1 versus a resistance-associated Th2-type response has been supplemented in recent years with cell populations such as novel innate lymphoid cells, basophils, dendritic cells and regulatory T cells proposed to play an active role in responses to T. muris infection. Moreover, new immune-controlled mechanisms of expulsion, such as increased epithelial cell turnover and mucin secretion, have been described in recent years increasing the number of possible targets for anti-parasite therapies. In this review, we give a comprehensive overview of experimental work conducted on the T. muris infection model, focusing on important findings and the most recent reports on the role of the immune system in parasite expulsion.


Assuntos
Gastroenteropatias/imunologia , Gastroenteropatias/parasitologia , Tricuríase/imunologia , Trichuris/imunologia , Imunidade Adaptativa , Animais , Gastroenteropatias/genética , Humanos , Imunidade Inata , Estágios do Ciclo de Vida , Tricuríase/genética , Trichuris/crescimento & desenvolvimento
8.
Immunobiology ; 217(12): 1259-65, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22902140

RESUMO

Regulation of an immune response requires complex crosstalk between cells of the innate and adaptive immune systems, via both cell-cell contact and secretion of cytokines. An important cytokine with a broad regulatory role in the immune system is transforming growth factor-ß (TGF-ß). TGF-ß is produced by and has effects on many different cells of the immune system, and plays fundamental roles in the regulation of immune responses during homeostasis, infection and disease. Although many cells can produce TGFß, it is always produced as an inactive complex that must be activated to bind to the TGFß receptor complex and promote downstream signalling. Thus, regulation of TGFß activation is a crucial step in controlling TGFß function. This review will discuss how TGFß controls diverse immune responses and how TGFß function is regulated, with a focus on recent work highlighting a critical role for the integrin αvß8 expressed by dendritic cells in activating TGFß.


Assuntos
Células Dendríticas/imunologia , Sistema Imunitário/imunologia , Integrinas/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Humanos
9.
Trends Biochem Sci ; 36(1): 47-54, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20870411

RESUMO

Transforming growth factor beta (TGFß) controls numerous cellular responses, including proliferation, differentiation, apoptosis and migration. This cytokine is produced by many different cell types and has been implicated in the pathogenesis of many diseases, ranging from autoimmune disorders and infectious diseases to fibrosis and cancer. However, TGFß is always produced as an inactive complex that must be activated to enable binding to its receptor and subsequent function. Recent evidence highlights a crucial role for members of the integrin receptor family in controlling the activation of TGFß. These pathways are important in human health and disease, and new insights into the biochemical mechanisms that allow integrins to control TGFß activation could prove useful in the design of therapeutics.


Assuntos
Integrinas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Humanos , Integrinas/imunologia , Ligação Proteica , Transdução de Sinais , Fator de Crescimento Transformador beta/química , Fator de Crescimento Transformador beta/imunologia
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