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1.
Mol Immunol ; 155: 1-6, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36634520

RESUMO

CD8 T cells play a critical role in immunity against intracellular pathogens and cancer. A primary objective of T cell-based vaccine strategies is the induction of durable and effective immune responses. Achieving this goal involves more than simply boosting the numbers of responding T cells. Of particular interest is the induction of CD8 T cells with polycytokine capability, specifically with the ability of CD8 T cells to co-produce IFNγ, TNFα and IL-2. The presence of these polycytokine-producing CD8 T cells correlates strongly with protection against foreign pathogens and cancer. Therefore, approaches capable of inducing such polyfunctional responses are needed. NKG2D engagement on CD8 T cells has been shown to result in increased effector response. However, the manner in which NKG2D engagement results in improved CD8 T cell effector response is unclear. Here we demonstrate in vitro and in vivo that NKG2D engagement by its natural ligand, Rae-1ε, shifts the balance from single cytokine to polycytokine (IL-2, IFNγ, and TFNα) production. These data define a previously unrecognized process in which NKG2D costimulation on CD8 T cells results in improved effector responses.


Assuntos
Citocinas , Neoplasias , Humanos , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Interleucina-2 , Linfócitos T CD8-Positivos
2.
Sci Rep ; 11(1): 13327, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172810

RESUMO

Adoptive T cell therapy with T cell receptor (TCR)-modified T cells has shown promise in treating metastatic melanoma and other malignancies. However, studies are needed to improve the efficacy and durability of responses of TCR-modified T cells. Standard protocols for generating TCR-modified T cells involve activating T cells through CD3 stimulation to allow for the efficient transfer of tumor-reactive receptors with viral vectors. T cell activation results in terminal differentiation and shortening of telomeres, which are likely suboptimal for therapy. In these studies, we demonstrate efficient T cell transduction with the melanoma-reactive TIL1383I TCR through culturing with interleukin 7 (IL-7) in the absence of CD3 activation. The TIL1383I TCR-modified T cells generated following IL-7 culture were enriched with naïve (TN) and memory stem cell populations (TSCM) while maintaining longer telomere lengths. Furthermore, we demonstrated melanoma-reactivity of TIL1383I TCR-modified cells generated following IL-7 culture using in vitro assays and a superior response in an in vivo melanoma model. These results suggest that utilizing IL-7 to generate TCR-modified T cells in the absence of activation is a feasible strategy to improve adoptive T cell therapies for melanoma and other malignancies.


Assuntos
Diferenciação Celular/imunologia , Ativação Linfocitária/imunologia , Melanoma/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular , Terapia Baseada em Transplante de Células e Tecidos/métodos , Feminino , Células HEK293 , Humanos , Memória Imunológica/imunologia , Interleucina-7/imunologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fenótipo , Transdução Genética/métodos
3.
Mol Ther Oncolytics ; 20: 352-363, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33614916

RESUMO

T cells that are gene-modified with tumor-specific T cell receptors are a promising treatment for metastatic melanoma patients. In a clinical trial, we treated seven metastatic melanoma patients with autologous T cells transduced to express a tyrosinase-reactive T cell receptor (TCR) (TIL 1383I) and a truncated CD34 molecule as a selection marker. We followed transgene expression in the TCR-transduced T cells after infusion and observed that both lentiviral- and retroviral-transduced T cells lost transgene expression over time, so that by 4 weeks post-transfer, few T cells expressed either lentiviral or retroviral transgenes. Transgene expression was reactivated by stimulation with anti-CD3/anti-CD28 beads and cytokines. TCR-transduced T cell lentiviral and retroviral transgene expression was also downregulated in vitro when T cells were cultured without cytokines. Transduced T cells cultured with interleukin (IL)-15 maintained transgene expression. Culturing gene-modified T cells in the presence of histone deacetylase (HDAC) inhibitors maintained transgene expression and functional TCR-transduced T cell responses to tumor. These results implicate epigenetic processes in the loss of transgene expression in lentiviral- and retroviral-transduced T cells.

5.
Melanoma Res ; 28(3): 171-184, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29521881

RESUMO

Immunotherapy is a promising method of treatment for a number of cancers. Many of the curative results have been seen specifically in advanced-stage melanoma. Despite this, single-agent therapies are only successful in a small percentage of patients, and relapse is very common. As chemotherapy is becoming a thing of the past for treatment of melanoma, the combination of cellular therapies with immunotherapies appears to be on the rise in in-vivo models and in clinical trials. These forms of therapies include tumor-infiltrating lymphocytes, T-cell receptor, or chimeric antigen receptor-modified T cells, cytokines [interleukin (IL-2), IL-15, IL-12, granulocyte-macrophage colony stimulating factor, tumor necrosis factor-α, interferon-α, interferon-γ], antibodies (αPD-1, αPD-L1, αTIM-3, αOX40, αCTLA-4, αLAG-3), dendritic cell-based vaccines, and chemokines (CXCR2). There are a substantial number of ongoing clinical trials using two or more of these combination therapies. Preliminary results indicate that these combination therapies are a promising area to focus on for cancer treatments, especially melanoma. The main challenges with the combination of cellular and immunotherapies are adverse events due to toxicities and autoimmunity. Identifying mechanisms for reducing or eliminating these adverse events remains a critical area of research. Many important questions still need to be elucidated in regard to combination cellular therapies and immunotherapies, but with the number of ongoing clinical trials, the future of curative melanoma therapies is promising.


Assuntos
Imunoterapia Adotiva/métodos , Melanoma/terapia , Neoplasias Cutâneas/terapia , Linfócitos T/imunologia , Terapia Combinada , Humanos , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/patologia , Estadiamento de Neoplasias , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia
6.
Am J Respir Cell Mol Biol ; 50(4): 787-95, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24199649

RESUMO

Gata5 is a transcription factor expressed in the lung, but its physiological role is unknown. To test whether and how Gata5 regulates airway constrictor responsiveness, we studied Gata5(-/-), Gata5(+/-), and wild-type mice on the C57BL/6J background. Cholinergic airway constrictor responsiveness was assessed invasively in mice without and with induction of allergic airway inflammation through ovalbumin sensitization and aerosol exposure. Gata5-deficient mice displayed native airway constrictor hyperresponsiveness (AHR) in the absence of allergen-induced inflammation. Gata5-deficient mice retained their relatively greater constrictor responsiveness even in ovalbumin-induced experimental asthma. Gata5 deficiency did not alter the distribution of cell types in bronchoalveolar lavage fluid, but bronchial epithelial mucus metaplasia was more prominent in Gata5(-/-) mice after allergen challenge. Gene expression profiles revealed that apolipoprotein E (apoE) was the fifth most down-regulated transcript in Gata5-deficient lungs, and quantitative RT-PCR and immunostaining confirmed reduced apoE expression in Gata5(-/-) mice. Quantitative RT-PCR also revealed increased IL-13 mRNA in the lungs of Gata5-deficient mice. These findings for the first time show that Gata5 regulates apoE and IL-13 expression in vivo and that its deletion causes AHR. Gata5-deficient mice exhibit an airway phenotype that closely resembles that previously reported for apoE(-/-) mice: both exhibit cholinergic AHR in native and experimental asthma states, and there is excessive goblet cell metaplasia after allergen sensitization and challenge. The Gata5-deficient phenotype also shares features that were previously reported for IL-13-treated mice. Together, these results indicate that Gata5 deficiency induces AHR, at least in part, by blunting apoE and increasing IL-13 expression.


Assuntos
Asma/metabolismo , Hiper-Reatividade Brônquica/metabolismo , Broncoconstrição , Fator de Transcrição GATA5/deficiência , Pulmão/metabolismo , Pneumonia/metabolismo , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Asma/induzido quimicamente , Asma/genética , Asma/fisiopatologia , Hiper-Reatividade Brônquica/induzido quimicamente , Hiper-Reatividade Brônquica/genética , Hiper-Reatividade Brônquica/fisiopatologia , Modelos Animais de Doenças , Fator de Transcrição GATA5/genética , Regulação da Expressão Gênica , Genótipo , Células Caliciformes/metabolismo , Células Caliciformes/patologia , Interleucina-13/genética , Interleucina-13/metabolismo , Pulmão/fisiopatologia , Metaplasia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Ovalbumina , Fenótipo , Pneumonia/induzido quimicamente , Pneumonia/genética , Pneumonia/fisiopatologia
7.
Am J Physiol Lung Cell Mol Physiol ; 305(10): L693-701, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24077945

RESUMO

T cell migration toward sites of antigen exposure is mediated by G protein signaling and is a key function in the development of immune responses. Regulators of G protein signaling (RGS) proteins modulate G protein signaling; however, their role in the regulation of adaptive immune responses has not been thoroughly explored. Herein we demonstrated abundant expression of the Gi/Gq-specific RGS3 in activated T cells, and that diminished RGS3 expression in a T cell thymoma increased cytokine-induced migration. To examine the role of endogenous RGS3 in vivo, mice deficient in the RGS domain (RGS3(ΔRGS)) were generated and tested in an experimental model of asthma. Compared with littermate controls, the inflammation in the RGS3(ΔRGS) mice was characterized by increased T cell numbers and the striking development of perivascular lymphoid structures. Surprisingly, while innate inflammatory cells were also increased in the lungs of RGS3(ΔRGS) mice, eosinophil numbers and Th2 cytokine production were equivalent to control mice. In contrast, T cell numbers in the draining lymph nodes (dLN) were reduced in the RGS3(ΔRGS), demonstrating a redistribution of T cells from the dLN to the lungs via increased RGS3(ΔRGS) T cell migration. Together these novel findings show a nonredundant role for endogenous RGS3 in controlling T cell migration in vitro and in an in vivo model of inflammation.


Assuntos
Movimento Celular , Inflamação/etiologia , Proteínas RGS/fisiologia , Mucosa Respiratória/imunologia , Linfócitos T/imunologia , Células Th2/imunologia , Animais , Apoptose , Western Blotting , Diferenciação Celular , Proliferação de Células , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pyroglyphidae/patogenicidade , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Células Th2/metabolismo , Células Th2/patologia
8.
PLoS One ; 8(8): e72955, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23967339

RESUMO

Acute rejection, a common complication of lung transplantation, may promote obliterative bronchiolitis leading to graft failure in lung transplant recipients. During acute rejection episodes, CD8(+) T cells can contribute to lung epithelial injury but the mechanisms promoting and controlling CD8-mediated injury in the lung are not well understood. To study the mechanisms regulating CD8(+) T cell-mediated lung rejection, we used a transgenic model in which adoptively transferred ovalbumin (OVA)-specific cytotoxic T lymphocytes (CTL) induce lung injury in mice expressing an ovalbumin transgene in the small airway epithelium of the lungs (CC10-OVA mice). The lung pathology is similar to findings in humans with acute lung transplant. In the presence of an intact immune response the inflammation resolves by day 30. Using CC10-OVA.RAG(-/-) mice, we found that CD4(+) T cells and ICOS(+/+) T cells were required for protection against lethal lung injury, while neutrophil depletion was not protective. In addition, CD4(+)Foxp3 (+) ICOS(+) T cells were enriched in the lungs of animals surviving lung injury and ICOS(+/+) Tregs promoted survival in animals that received ICOS(-/-) T cells. Direct comparison of ICOS(-/-) Tregs to ICOS(+/+) Tregs found defects in vitro but no differences in the ability of ICOS(-/-) Tregs to protect from lethal lung injury. These data suggest that ICOS affects Treg development but is not necessarily required for Treg effector function.


Assuntos
Rejeição de Enxerto/genética , Rejeição de Enxerto/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Lesão Pulmonar/genética , Lesão Pulmonar/imunologia , Transplante de Pulmão/efeitos adversos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Animais , Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Modelos Animais de Doenças , Expressão Gênica , Técnicas de Silenciamento de Genes , Rejeição de Enxerto/mortalidade , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Interleucina-10/metabolismo , Interleucina-2/metabolismo , Lesão Pulmonar/patologia , Subpopulações de Linfócitos/citologia , Camundongos , Neutrófilos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
9.
J Immunol ; 188(8): 3639-47, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22430740

RESUMO

CD8(+) T cell responses have been shown to be regulated by dendritic cells (DCs) and CD4(+) T cells, leading to the tenet that CD8(+) T cells play a passive role in their own differentiation. In contrast, by using a DNA vaccination model, to separate the events of vaccination from those of CD8(+) T cell priming, we demonstrate that CD8(+) T cells, themselves, actively limit their own memory potential through CD8(+) T cell-derived IFN-γ-dependent modification of the IL-12/IL-15Rα axis on DCs. Such CD8(+) T cell-driven cytokine alterations result in increased T-bet and decreased Bcl-2 expression, and thus decreased memory progenitor formation. These results identify an unrecognized role for CD8(+) T cells in the regulation of their own effector differentiation fate and a previously uncharacterized relationship between the balance of inflammation and memory formation.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Memória Imunológica , Receptores de Interleucina-12/imunologia , Receptores de Interleucina-15/imunologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/imunologia , Células Dendríticas/metabolismo , Regulação da Expressão Gênica/imunologia , Humanos , Interferon gama , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-15/genética , Interleucina-15/imunologia , Ativação Linfocitária , Melanoma Experimental/imunologia , Melanoma Experimental/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-12/genética , Receptores de Interleucina-15/genética , Transdução de Sinais/imunologia , Vacinação , Vacinas de DNA/imunologia
10.
Nat Med ; 18(3): 422-8, 2012 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-22366950

RESUMO

CD4-unhelped CD8(+) T cells are functionally defective T cells primed in the absence of CD4(+) T cell help. Given the co-stimulatory role of natural-killer group 2, member D protein (NKG2D) on CD8(+) T cells, we investigated its ability to rescue these immunologically impotent cells. We demonstrate that augmented co-stimulation through NKG2D during priming paradoxically rescues memory, but not effector, CD8(+) T cell responses. NKG2D-mediated rescue is characterized by reversal of elevated transcription factor T-box expressed in T cells (T-bet) expression and recovery of interleukin-2 and interferon-γ production and cytolytic responses. Rescue is abrogated in CD8(+) T cells lacking NKG2D. Augmented co-stimulation through NKG2D confers a high rate of survival to mice lacking CD4(+) T cells in a CD4-dependent influenza model and rescues HIV-specific CD8(+) T cell responses from CD4-deficient HIV-positive donors. These findings demonstrate that augmented co-stimulation through NKG2D is effective in rescuing CD4-unhelped CD8(+) T cells from their pathophysiological fate and may provide therapeutic benefits.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Influenza Humana/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Citotoxicidade Imunológica , Modelos Animais de Doenças , Expressão Gênica , HIV-1/imunologia , Humanos , Imunidade Celular , Influenza Humana/genética , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-2/imunologia , Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Proteínas com Domínio T/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Vacinas de DNA/imunologia
11.
Autoimmunity ; 44(8): 599-606, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21913803

RESUMO

In this study, we demonstrate that engagement of two different natural killer receptors (NKRs) can lead to contrasting effects in the development of self-reactive CD8+T cells and autoimmune vitiligo. Specifically, using a mouse model, we show that CD8+T-cell targeting of a melanocyte antigen, tyrosinase-related protein-1 (TRP-1) in combination with delivery of the NKG2D ligands (Rae-1ϵ or H60), results in strong CD8+T-cell responses against TRP-1 and in the development of autoimmune vitiligo. In contrast, targeting of TRP-1 in combination with delivery of CD48, the natural ligand for the NKR 2B4, leads to reduced formation of TRP-1-reactive CD8+T-cell responses and decreased development of vitiligo. These data indicate that autoimmune vitiligo is limited by insufficient signals, despite plentiful self-reactive T cells in the peripheral immune system. To our knowledge, this is the first experimental evidence supporting the role of NKRs in modulating CD8+T-cell autoimmune vitiligo. This study supports the utilization of NKR signaling as a therapeutic avenue toward prevention of vitiligo and other autoimmune diseases.


Assuntos
Antígenos CD/metabolismo , Doenças Autoimunes/imunologia , Linfócitos T CD8-Positivos/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptores Imunológicos/metabolismo , Vitiligo/imunologia , Animais , Antígenos CD/genética , Doenças Autoimunes/metabolismo , Antígeno CD48 , Linfócitos T CD8-Positivos/metabolismo , Ligantes , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Oxirredutases/genética , Oxirredutases/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária , Vitiligo/metabolismo
12.
Cancer Immunol Immunother ; 60(11): 1543-51, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21681376

RESUMO

While the effects of TCR affinity and TGFß on CD8(+) T-cell function have been studied individually, the manner in which TCR affinity dictates susceptibility to TGFß-mediated suppression remains unknown. To address this issue, we utilized OVA altered peptide ligands (APLs) of different affinities in the OT-I model. We demonstrate that while decreased TCR ligand affinity initially results in weakened responses, such interactions prime the resultant effector cells to respond more strongly to cognate antigen upon secondary exposure. Despite this, responses by CD8(+) T cells primed with lower-affinity TCR ligands are more effectively regulated by TGFß. Susceptibility to TGFß-mediated suppression is associated with downregulation of RGS3, a recently recognized negative regulator of TGFß signaling, but not expression of TGFß receptors I/II. These results suggest a novel tolerance mechanism whereby CD8(+) T cells are discriminately regulated by TGFß according to the affinity of the ligand on which they were initially primed. In addition, because of the major role played by TGFß in tumor-induced immune suppression, these results identify the affinity of the priming ligand as a primary concern in CD8(+) T-cell-mediated cancer immunotherapeutic strategies.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Oligopeptídeos/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Regulação para Baixo , Proteínas de Ligação ao GTP/biossíntese , Proteínas de Ligação ao GTP/imunologia , Proteínas Ativadoras de GTPase/biossíntese , Proteínas Ativadoras de GTPase/imunologia , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Oligopeptídeos/farmacologia , Proteínas RGS , Transdução de Sinais , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/farmacologia
13.
PLoS One ; 6(2): e16529, 2011 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-21364749

RESUMO

Memory CD4 T cells play a vital role in protection against re-infection by pathogens as diverse as helminthes or influenza viruses. Inducible costimulator (ICOS) is highly expressed on memory CD4 T cells and has been shown to augment proliferation and survival of activated CD4 T cells. However, the role of ICOS costimulation on the development and maintenance of memory CD4 T cells remains controversial. Herein, we describe a significant defect in the number of effector memory (EM) phenotype cells in ICOS(-/-) and ICOSL(-/-) mice that becomes progressively more dramatic as the mice age. This decrease was not due to a defect in the homeostatic proliferation of EM phenotype CD4 T cells in ICOS(-/-) or ICOSL(-/-) mice. To determine whether ICOS regulated the development or survival of EM CD4 T cells, we utilized an adoptive transfer model. We found no defect in development of EM CD4 T cells, but long-term survival of ICOS(-/-) EM CD4 T cells was significantly compromised compared to wild-type cells. The defect in survival was specific to EM cells as the central memory (CM) ICOS(-/-) CD4 T cells persisted as well as wild type cells. To determine the physiological consequences of a specific defect in EM CD4 T cells, wild-type and ICOS(-/-) mice were infected with influenza virus. ICOS(-/-) mice developed significantly fewer influenza-specific EM CD4 T cells and were more susceptible to re-infection than wild-type mice. Collectively, our findings demonstrate a role for ICOS costimulation in the maintenance of EM but not CM CD4 T cells.


Assuntos
Antígenos de Diferenciação de Linfócitos T/fisiologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/fisiologia , Memória Imunológica/genética , Proteínas/fisiologia , Animais , Antígenos de Diferenciação de Linfócitos T/genética , Linfócitos T CD4-Positivos/metabolismo , Sobrevivência Celular/genética , Citoproteção/genética , Citoproteção/imunologia , Predisposição Genética para Doença , Memória Imunológica/fisiologia , Ligante Coestimulador de Linfócitos T Induzíveis , Proteína Coestimuladora de Linfócitos T Induzíveis , Vírus da Influenza A/fisiologia , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/imunologia , Fenótipo , Proteínas/genética
14.
Am J Respir Cell Mol Biol ; 45(4): 843-50, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21421907

RESUMO

We and others reported that inducible costimulator-deficient (ICOS(-/-)) mice manifest a defect in Th2-mediated airway inflammation, which was attributed to reduced Th2 differentiation in the absence of ICOS signaling. Interestingly, the number of CD4 T cells present in the airways and lungs after sensitization and challenge is significantly reduced in ICOS(-/-) mice. We now show that this reduction is not attributable simply to a reduced proliferation of ICOS(-/-) cells, because significantly more ICOS(-/-) than wild-type activated CD4 T cells are present in the lymph nodes, suggesting that more ICOS(-/-) CD4 T cells than wild-type CD4 T cells migrated into the lymph nodes. Further investigation revealed that activated ICOS(-/-) CD4 T cells express higher concentrations of the lymph node homing receptors, CCR7 and CD62L, than do wild-type CD4 T cells, leading to a preferential return of ICOS(-/-) cells to the nondraining lymph nodes rather than the lungs. Blocking reentry into the lymph nodes after the initiation of Th2-mediated airway inflammation equalized the levels of CD4 and granulocyte infiltration in the lungs of wild-type and ICOS(-/-) mice. Our results demonstrate that in wild-type CD4 T cells, co-stimulation with ICOS promotes the down-regulation of CCR7 and CD62L after activation, leading to a reduced return of activated CD4 T cells to the lymph nodes and a more efficient entry into the lungs.


Assuntos
Antígenos de Diferenciação de Linfócitos T/metabolismo , Linfócitos T CD4-Positivos/imunologia , Quimiotaxia de Leucócito , Selectina L/metabolismo , Pulmão/imunologia , Pneumonia/imunologia , Receptores CCR7/metabolismo , Transferência Adotiva , Animais , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Helmintos/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Linfócitos T CD4-Positivos/transplante , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo , Proteína Coestimuladora de Linfócitos T Induzíveis , Linfonodos/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/genética , Schistosoma mansoni/imunologia , Células Th2/imunologia , Fatores de Tempo
15.
Am J Respir Cell Mol Biol ; 43(3): 342-8, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19855087

RESUMO

Our previous studies revealed that, in a murine model of asthma, mice that received Fas-deficient T cells developed a prolonged phase of airway inflammation, mucus production, and airway hyperreactivity that failed to resolve even 6 weeks after the last challenge. To investigate how Fas-Fas ligand (FasL) interaction occurs between T cells and other cells in vivo, Gld mice with abnormalities of the FasL signaling pathway were used. The reconstituted mice were made by transferring T cells from B6 or Gld mice to Rag(-/-) or FasL-deficient Rag(-/-) mice. We found that Rag(-/-) mice that received B6 T cells resolved the airway inflammation, whereas FasL-deficient Rag(-/-) mice that received Gld T cells developed a prolonged airway inflammation at Day 28, with decreased IFN-gamma production. Both FasL-deficient Rag(-/-) mice that received B6 T cells and Rag(-/-) mice that received Gld T cells also had completely resolved their airway inflammation by Day 28 after challenge. Interestingly, FasL-deficient Rag(-/-) mice that received Gld T cells eventually resolved airway inflammation at Day 42, with a similar level of IFN-gamma production to that of control group. These results demonstrate that FasL expression on either T cells only or non-T cells only was sufficient for the eventual resolution of airway inflammation, and the prolonged airway inflammation in FasL-deficient Rag(-/-) mice that received Gld T cells was correlated with decreased IFN-gamma production by Gld T cells.


Assuntos
Asma/prevenção & controle , Modelos Animais de Doenças , Proteína Ligante Fas/fisiologia , Sistema Respiratório/metabolismo , Linfócitos T/metabolismo , Transferência Adotiva , Animais , Asma/imunologia , Asma/metabolismo , Células Cultivadas , Citocinas/metabolismo , Citometria de Fluxo , Proteínas de Homeodomínio/fisiologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/transplante
16.
PLoS One ; 4(11): e7525, 2009 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-19888475

RESUMO

BACKGROUND: Inducible Costimulator (ICOS) is an important regulator of Th2 lymphocyte function and a potential immunotherapeutic target for allergy and asthma. A SNP in the ICOS 5' promoter in humans is associated with increased atopy and serum IgE in a founder population and increased ICOS surface expression and Th2 cytokine production from peripheral blood mononuclear cells. However, it is unknown if increased ICOS expression contributes to disease progression or is a result of disease pathology. METHODOLOGY/PRINCIPAL FINDINGS: We developed a mouse model in which ICOS surface expression levels are genetically predetermined to test our hypothesis that genetic regulation of ICOS expression controls the severity of Th2 responses in vivo. Using ICOS+/+ and ICOS+/- mice in a Th2 model of airway inflammation, we found that T cells from the ICOS+/- mice had reduced ICOS expression and decreased Th2-mediated inflammation in vivo. Although the activation status of the T cells did not differ, T cells isolated from the lungs and draining lymph nodes of ICOS+/- mice at the peak of inflammation produced less Th2 cytokines upon stimulation ex vivo. Using 4get mice, which express GFP upon IL-4 transcription, we determined that the decreased Th2 cytokines in ICOS+/- is due to reduced percentage of Th2 cells and not a defect in their ability to produce IL-4. CONCLUSION: These data suggest that in both mice and humans, the level of ICOS surface expression regulates the magnitude of the in vivo Th2 response, perhaps by influencing Th2 differentiation.


Assuntos
Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/fisiologia , Regulação da Expressão Gênica , Células Th2/citologia , Transcrição Gênica , Animais , Células Apresentadoras de Antígenos , Membrana Celular/metabolismo , Citocinas/metabolismo , Progressão da Doença , Feminino , Proteína Coestimuladora de Linfócitos T Induzíveis , Inflamação , Interleucina-4/metabolismo , Leucócitos Mononucleares/citologia , Linfonodos/metabolismo , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
17.
Cell Immunol ; 259(2): 177-84, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19646680

RESUMO

Previous work has shown ICOS can function independently of CD28, but whether either molecule can compensate for the other in vivo is not known. Since ICOS is a potent inducer of Th2 cytokines and linked to allergy and elevated serum IgE in humans, we hypothesized that augmenting ICOS costimulation in murine allergic airway disease may overcome CD28 deficiency. While ICOS was expressed on T cells from CD28(-/-) mice, Th2-mediated airway inflammation was not induced in CD28(-/-) mice by increased ICOS costimulation. Further, we determined if augmenting CD28 costimulation could compensate for ICOS deficiency. ICOS(-/-) mice had a defect in airway eosinophilia that was not overcome by augmenting CD28 costimulation. CD28 costimulation also did not fully compensate for ICOS for antibody responses, germinal center formation or the development of follicular B helper T cells. CD28 and ICOS play complementary non-overlapping roles in the development of Th2 immunity in vivo.


Assuntos
Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos CD28/imunologia , Pneumopatias/imunologia , Células Th2/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Histocitoquímica , Imunidade Celular/imunologia , Imunoglobulina E/sangue , Proteína Coestimuladora de Linfócitos T Induzíveis , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Organismos Livres de Patógenos Específicos
18.
Cancer Immunol Immunother ; 58(5): 719-28, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-18836717

RESUMO

Effective immunotherapy using T cell receptor (TCR) gene-modified T cells requires an understanding of the relationship between TCR affinity and functional avidity of T cells. In this study, we evaluate the relative affinity of two TCRs isolated from HLA-A2-restricted, gp100-reactive T cell clones with extremely high functional avidity. Furthermore, one of these T cell clones, was CD4- CD8- indicating that antigen recognition by this clone was CD8 independent. However, when these TCRs were expressed in CD8- Jurkat cells, the resulting Jurkat cells recognized gp100:209-217 peptide loaded T2 cells and had high functional avidity, but could not recognize HLA-A2+ melanoma cells expressing gp100. Tumor cell recognition by Jurkat cells expressing these TCRs could not be induced by exogenously loading the tumor cells with the native gp100:209-217 peptide. These results indicate that functional avidity of a T cell does not necessarily correlate with TCR affinity and CD8-independent antigen recognition by a T cell does not always mean its TCR will transfer CD8-independence to other effector cells. The implications of these findings are that T cells can modulate their functional avidity independent of the affinity of their TCRs.


Assuntos
Apresentação de Antígeno , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Glicoproteínas de Membrana/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Antígenos CD/análise , Vacinas Anticâncer/uso terapêutico , Linhagem Celular Tumoral/imunologia , Células Clonais/imunologia , Células Clonais/metabolismo , Citotoxicidade Imunológica , Epitopos de Linfócito T/imunologia , Rearranjo Gênico do Linfócito T , Antígeno HLA-A2/imunologia , Humanos , Imunofenotipagem , Imunoterapia Ativa , Células Jurkat , Melanoma/sangue , Melanoma/terapia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Proteínas Recombinantes de Fusão/imunologia , Antígeno gp100 de Melanoma
19.
Cancer Immunol Immunother ; 58(5): 709-18, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-18836718

RESUMO

The immune attack against malignant tumors require the concerted action of CD8+ cytotoxic T lymphocytes (CTL) as well as CD4+ T helper cells. The contribution of T cell receptor (TCR) alphabeta+ CD4- CD8- double-negative (DN) T cells to anti-tumor immune responses is widely unknown. In previous studies, we have demonstrated that DN T cells with a broad TCR repertoire are present in humans in the peripheral blood and the lymph nodes of healthy individuals. Here, we characterize a human DN T cell clone (T4H2) recognizing an HLA-A2-restricted melanoma-associated antigenic gp100-peptide isolated from the peripheral blood of a melanoma patient. Antigen recognition by the T4H2 DN clone resulted in specific secretion of IFN-gamma and TNF. Although lacking the CD8 molecule the gp100-specific DN T cell clone was able to confer antigen-specific cytotoxicity against gp100-loaded target cells as well as HLA-A2+ gp100 expressing melanoma cells. The cytotoxic capacity was found to be perforin/granzymeB-dependent. Together, these data indicate that functionally active antigen-specific DN T cells recognizing MHC class I-restricted tumor-associated antigen (TAA) may contribute to anti-tumor immunity in vivo.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Imunoterapia Ativa , Melanoma/imunologia , Glicoproteínas de Membrana/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Apresentação de Antígeno , Antígenos CD/análise , Vacinas Anticâncer/uso terapêutico , Linhagem Celular Tumoral/imunologia , Células Clonais/imunologia , Células Clonais/metabolismo , Citotoxicidade Imunológica , Granzimas/imunologia , Antígeno HLA-A2/imunologia , Humanos , Imunofenotipagem , Interferon gama/metabolismo , Interleucinas/metabolismo , Melanoma/sangue , Melanoma/terapia , Perforina/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/análise , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Citotóxicos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Antígeno gp100 de Melanoma
20.
J Immunol ; 181(2): 1019-24, 2008 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-18606653

RESUMO

The T cell costimulatory molecule ICOS regulates Th2 effector function in allergic airway disease. Recently, several studies with ICOS(-/-) mice have also demonstrated a role for ICOS in Th2 differentiation. To determine the effects of ICOS on the early immune response, we investigated augmenting ICOS costimulation in a Th2-mediated immune response to Schistosoma mansoni Ags. We found that augmenting ICOS costimulation with B7RP-1-Fc increased the accumulation of T and B cells in the draining lymph nodes postimmunization. Interestingly, the increased numbers were due in part to increased migration of undivided Ag-specific TCR transgenic T cells and surprisingly B cells, as well as non-TCR transgenic T cells. B7RP-1-Fc also increased the levels of the chemokines CCL21 and CXCL13 in the draining lymph node, suggesting ICOS costimulation contributes to migration by direct or indirect effects on dendritic cells, stromal cells and high endothelial venules. Further, the effects of B7RP-1-Fc were not dependent on immunization. Our data support a model in which ICOS costimulation augments the pool of lymphocytes in the draining lymph nodes, leading to an increase in the frequency of potentially reactive T and B cells.


Assuntos
Antígenos de Diferenciação de Linfócitos T/imunologia , Antígeno B7-1/imunologia , Citocinas/metabolismo , Linfonodos/imunologia , Linfócitos/imunologia , Schistosoma mansoni/imunologia , Células Th2/imunologia , Animais , Antígenos de Diferenciação de Linfócitos T/metabolismo , Linfócitos B/imunologia , Antígeno B7-1/metabolismo , Movimento Celular , Citocinas/imunologia , Feminino , Ligante Coestimulador de Linfócitos T Induzíveis , Proteína Coestimuladora de Linfócitos T Induzíveis , Linfonodos/citologia , Linfonodos/metabolismo , Linfócitos/citologia , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Linfócitos T/imunologia
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