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1.
Sci Transl Med ; 13(581)2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597266

RESUMO

Although immune checkpoint inhibitors (ICIs), such as anti-programmed cell death protein-1 (PD-1), can deliver durable antitumor effects, most patients with cancer fail to respond. Recent studies suggest that ICI efficacy correlates with a higher load of tumor-specific neoantigens and development of vitiligo in patients with melanoma. Here, we report that patients with low melanoma neoantigen burdens who responded to ICI had tumors with higher expression of pigmentation-related genes. Moreover, expansion of peripheral blood CD8+ T cell populations specific for melanocyte antigens was observed only in patients who responded to anti-PD-1 therapy, suggesting that ICI can promote breakdown of tolerance toward tumor-lineage self-antigens. In a mouse model of poorly immunogenic melanomas, spreading of epitope recognition toward wild-type melanocyte antigens was associated with markedly improved anti-PD-1 efficacy in two independent approaches: introduction of neoantigens by ultraviolet (UV) B radiation mutagenesis or the therapeutic combination of ablative fractional photothermolysis plus imiquimod. Complete responses against UV mutation-bearing tumors after anti-PD-1 resulted in protection from subsequent engraftment of melanomas lacking any shared neoantigens, as well as pancreatic adenocarcinomas forcibly overexpressing melanocyte-lineage antigens. Our data demonstrate that somatic mutations are sufficient to provoke strong antitumor responses after checkpoint blockade, but long-term responses are not restricted to these putative neoantigens. Epitope spreading toward T cell recognition of wild-type tumor-lineage self-antigens represents a common pathway for successful response to ICI, which can be evoked in neoantigen-deficient tumors by combination therapy with ablative fractional photothermolysis and imiquimod.

2.
Sci Immunol ; 6(55)2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33452106

RESUMO

The developmental origins of memory T cells remain incompletely understood. During the expansion phase of acute viral infection, we identified a distinct subset of virus-specific CD8+ T cells that possessed distinct characteristics including expression of CD62L, T cell factor 1 (TCF-1), and Eomesodermin; relative quiescence; expression of activation markers; and features of limited effector differentiation. These cells were a quantitatively minor subpopulation of the TCF-1+ pool and exhibited self-renewal, heightened DNA damage surveillance activity, and preferential long-term recall capacity. Despite features of memory and somewhat restrained proliferation during the expansion phase, this subset displayed evidence of stronger TCR signaling than other responding CD8+ T cells, coupled with elevated expression of multiple inhibitory receptors including programmed cell death 1 (PD-1), lymphocyte activating gene 3 (LAG-3), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), CD5, and CD160. Genetic ablation of PD-1 and LAG-3 compromised the formation of this CD62Lhi TCF-1+ subset and subsequent CD8+ T cell memory. Although central memory phenotype CD8+ T cells were formed in the absence of these cells, subsequent memory CD8+ T cell recall responses were compromised. Together, these results identify an important link between genome integrity maintenance and CD8+ T cell memory. Moreover, the data indicate a role for inhibitory receptors in preserving key memory CD8+ T cell precursors during initial activation and differentiation. Identification of this rare subpopulation within the memory CD8+ T cell precursor pool may help reconcile models of the developmental origin of long-term CD8+ T cell memory.

3.
Proc Natl Acad Sci U S A ; 117(38): 23684-23694, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32907939

RESUMO

Immune checkpoint blockade (ICB) is efficacious in many diverse cancer types, but not all patients respond. It is important to understand the mechanisms driving resistance to these treatments and to identify predictive biomarkers of response to provide best treatment options for all patients. Here we introduce a resection and response-assessment approach for studying the tumor microenvironment before or shortly after treatment initiation to identify predictive biomarkers differentiating responders from nonresponders. Our approach builds on a bilateral tumor implantation technique in a murine metastatic breast cancer model (E0771) coupled with anti-PD-1 therapy. Using our model, we show that tumors from mice responding to ICB therapy had significantly higher CD8+ T cells and fewer Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs) at early time points following therapy initiation. RNA sequencing on the intratumoral CD8+ T cells identified the presence of T cell exhaustion pathways in nonresponding tumors and T cell activation in responding tumors. Strikingly, we showed that our derived response and resistance signatures significantly segregate patients by survival and associate with patient response to ICB. Furthermore, we identified decreased expression of CXCR3 in nonresponding mice and showed that tumors grown in Cxcr3 -/- mice had an elevated resistance rate to anti-PD-1 treatment. Our findings suggest that the resection and response tumor model can be used to identify response and resistance biomarkers to ICB therapy and guide the use of combination therapy to further boost the antitumor efficacy of ICB.


Assuntos
Neoplasias da Mama , Imunoterapia , Neoplasias Mamárias Experimentais , Microambiente Tumoral/imunologia , Animais , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Linfócitos T CD8-Positivos/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Transcriptoma/imunologia
4.
Cell Rep ; 31(13): 107827, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32610128

RESUMO

The PD-1 pathway regulates dysfunctional T cells in chronic infection and cancer, but the role of this pathway during acute infection remains less clear. Here, we demonstrate that PD-1 signals are needed for optimal memory. Mice deficient in the PD-1 pathway exhibit impaired CD8+ T cell memory following acute influenza infection, including reduced virus-specific CD8+ T cell numbers and compromised recall responses. PD-1 blockade during priming leads to similar differences early post-infection but without the defect in memory formation, suggesting that timing and/or duration of PD-1 blockade could be tailored to modulate host responses. Our studies reveal a role for PD-1 as an integrator of CD8+ T cell signals that promotes CD8+ T cell memory formation and suggest PD-1 continues to fine-tune CD8+ T cells after they migrate into non-lymphoid tissues. These findings have important implications for PD-1-based immunotherapy, in which PD-1 inhibition may influence memory responses in patients.

5.
Trends Immunol ; 40(6): 511-523, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31053497

RESUMO

Oncology has recently undergone a revolutionary change with widespread adoption of immunotherapy for many cancers. Immunotherapy using monoclonal antibodies against checkpoint molecules, including programmed death (PD)-1, PD ligand (PD-L)1, and cytotoxic T lymphocyte-associated antigen (CTLA)-4, is effective in a significant subset of patients. However, immune-related adverse events (irAEs) have emerged as frequent complications of checkpoint blockade, likely due to the physiological role of checkpoint pathways in regulating adaptive immunity and preventing autoimmunity. As immunotherapy becomes more common, a better understanding of the etiology of irAEs and ways to limit these events is needed. At the same time, studying these new therapy-related disorders provides an opportunity to better understand naturally occurring human autoimmune and inflammatory disorders, with the potential to improve therapies for cancer and autoimmune diseases.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Imunoterapia/efeitos adversos , Neoplasias/terapia , Animais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Autoimunidade , Biomarcadores Tumorais , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Imunomodulação/efeitos dos fármacos , Imunoterapia/métodos , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Avaliação de Resultados da Assistência ao Paciente , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
6.
Sci Rep ; 8(1): 8295, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29844327

RESUMO

Type 1 diabetes is caused by autoreactive T cell-mediated ß cell destruction. Even though co-inhibitory receptor programmed death-1 (PD-1) restrains autoimmunity, the expression and regulation of its cognate ligands on ß cell remains unknown. Here, we interrogated ß cell-intrinsic programmed death ligand-1 (PD-L1) expression in mouse and human islets. We measured a significant increase in the level of PD-L1 surface expression and the frequency of PD-L1+ ß cells as non-obese diabetic (NOD) mice aged and developed diabetes. Increased ß cell PD-L1 expression was dependent on T cell infiltration, as ß cells from Rag1-deficient mice lacked PD-L1. Using Rag1-deficient NOD mouse islets, we determined that IFN-γ promotes ß cell PD-L1 expression. We performed analogous experiments using human samples, and found a significant increase in ß cell PD-L1 expression in type 1 diabetic samples compared to type 2 diabetic, autoantibody positive, and non-diabetic samples. Among type 1 diabetic samples, ß cell PD-L1 expression correlated with insulitis. In vitro experiments with human islets from non-diabetic individuals showed that IFN-γ promoted ß cell PD-L1 expression. These results suggest that insulin-producing ß cells respond to pancreatic inflammation and IFN-γ production by upregulating PD-L1 expression to limit self-reactive T cells.


Assuntos
Antígeno B7-H1/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Interferon gama/metabolismo , Ilhotas Pancreáticas/metabolismo , Linfócitos T/imunologia , Animais , Feminino , Humanos , Interferon gama/biossíntese , Ilhotas Pancreáticas/imunologia , Camundongos , Camundongos Endogâmicos NOD
7.
Nat Rev Immunol ; 18(3): 153-167, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28990585

RESUMO

T cell activation is a highly regulated process involving peptide-MHC engagement of the T cell receptor and positive costimulatory signals. Upon activation, coinhibitory 'checkpoints', including programmed cell death protein 1 (PD1), become induced to regulate T cells. PD1 has an essential role in balancing protective immunity and immunopathology, homeostasis and tolerance. However, during responses to chronic pathogens and tumours, PD1 expression can limit protective immunity. Recently developed PD1 pathway inhibitors have revolutionized cancer treatment for some patients, but the majority of patients do not show complete responses, and adverse events have been noted. This Review discusses the diverse roles of the PD1 pathway in regulating immune responses and how this knowledge can improve cancer immunotherapy as well as restore and/or maintain tolerance during autoimmunity and transplantation.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Imunoterapia/métodos , Ativação Linfocitária/imunologia , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Autoimunidade/imunologia , Linfócitos B/imunologia , Humanos , Células Matadoras Naturais/imunologia , Transdução de Sinais/imunologia
8.
Nature ; 545(7652): 60-65, 2017 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-28397821

RESUMO

Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Melanoma/tratamento farmacológico , Melanoma/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Carga Tumoral/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Feminino , Humanos , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo , Masculino , Melanoma/irrigação sanguínea , Melanoma/patologia , Estadiamento de Neoplasias , Fenótipo , Resultado do Tratamento
9.
Cell ; 167(6): 1540-1554.e12, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27912061

RESUMO

Therapeutic blocking of the PD1 pathway results in significant tumor responses, but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB) and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies.


Assuntos
Antígeno CTLA-4/antagonistas & inibidores , Melanoma/imunologia , Melanoma/terapia , Radioimunoterapia , Animais , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Xenoenxertos , Humanos , Interferons/imunologia , Melanoma/tratamento farmacológico , Melanoma/radioterapia , Camundongos , Transplante de Neoplasias , Fator de Transcrição STAT1 , Linfócitos T/imunologia
10.
Science ; 354(6316): 1160-1165, 2016 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-27789795

RESUMO

Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEX into durable memory T cells (TMEM) is unclear. We found that reinvigoration of TEX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated TEX became reexhausted if antigen concentration remained high and failed to become TMEM upon antigen clearance. TEX acquired an epigenetic profile distinct from that of effector T cells (TEFF) and TMEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that TEX are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the TEX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.


Assuntos
Antígeno B7-H1/genética , Linfócitos T CD8-Positivos/imunologia , Reprogramação Celular/genética , Epigênese Genética , Memória Imunológica/genética , Animais , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/transplante , Linhagem da Célula/genética , Reprogramação Celular/imunologia , Feminino , Redes Reguladoras de Genes , Imunoterapia , Interleucina-7/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transcrição Genética
11.
Artigo em Inglês | MEDLINE | ID: mdl-27656680

RESUMO

Type 1 diabetes (T1D) is a CD4+ T cell-driven autoimmune disease resulting from the destruction of insulin-producing pancreatic beta cells. Clinical evidence and studies in non-obese diabetic (NOD) mice suggest that insulin is a major autoantigen. With this in mind, we developed insulin B10-23:IAg7 tetramer reagents to track insulin-specific CD4+ T cells in mice and interrogated the role of Programmed death-1 (PD-1) for peripheral tolerance. PD-1 is a T cell inhibitory receptor necessary to maintain tolerance and prevent T1D in NOD mice. PD-1 pathway inhibitors are increasingly used in the clinic for treating malignancies, and while many patients benefit, some develop adverse autoimmune events, including T1D. We therefore sought to understand the role of PD-1 in maintaining islet-specific tolerance in diabetes-resistant strains. B6.g7 mice express the same MHC Class II allele as NOD mice, have predominantly naïve insulin-specific CD4+ T cells in the periphery, and remain diabetes-free even after PD-1 pathway blockade. Here, we examined the trafficking potential of insulin-specific CD4+ T cells in NOD and B6.g7 mice with or without anti-PD-L1 treatment, and found that PD-L1 blockade preferentially increased the number of CD44highCXCR3+ insulin-specific cells in NOD but not B6.g7 mice. Additionally, we investigated whether pancreatic islets in NOD and B6.g7 mice expressed CXCL10, a lymphocyte homing chemokine and ligand for CXCR3. Anti-PD-L1 treated and control NOD mice had detectable CXCL10 expression in the islets, while B6.g7 islets did not. These data suggest that islet tolerance may be in part attributed to the pancreatic environment and in the absence of pancreas inflammation, chemotactic cytokines may be missing. This, together with our previous data showing that PD-1 pathway blockade preferentially affects effector but not anergic self-specific T cells has implications for the use of checkpoint blockade in treating tumor patients. Our work suggests that determining tumor- and self-specific CD4+ T cell activation status (naïve, effector or anergic) prior to initiation of immunotherapy would likely help to stratify individuals who would benefit from this therapy versus those who might have adverse effects or incomplete tumor control.

12.
Immunity ; 45(2): 358-73, 2016 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-27496729

RESUMO

Dynamic reprogramming of metabolism is essential for T cell effector function and memory formation. However, the regulation of metabolism in exhausted CD8(+) T (Tex) cells is poorly understood. We found that during the first week of chronic lymphocytic choriomeningitis virus (LCMV) infection, before severe dysfunction develops, virus-specific CD8(+) T cells were already unable to match the bioenergetics of effector T cells generated during acute infection. Suppression of T cell bioenergetics involved restricted glucose uptake and use, despite persisting mechanistic target of rapamycin (mTOR) signaling and upregulation of many anabolic pathways. PD-1 regulated early glycolytic and mitochondrial alterations and repressed transcriptional coactivator PGC-1α. Improving bioenergetics by overexpression of PGC-1α enhanced function in developing Tex cells. Therapeutic reinvigoration by anti-PD-L1 reprogrammed metabolism in a subset of Tex cells. These data highlight a key metabolic control event early in exhaustion and suggest that manipulating glycolytic and mitochondrial metabolism might enhance checkpoint blockade outcomes.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Animais , Anticorpos Neutralizantes/farmacologia , Antígeno B7-H1/imunologia , Células Cultivadas , Reprogramação Celular , Senescência Celular , Metabolismo Energético , Glucose/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Receptor de Morte Celular Programada 1/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
13.
J Immunol ; 196(11): 4793-804, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27183622

RESUMO

Checkpoint blockade-based immunotherapies are effective in cancers with high numbers of nonsynonymous mutations. In contrast, current paradigms suggest that such approaches will be ineffective in cancers with few nonsynonymous mutations. To examine this issue, we made use of a murine model of BCR-ABL(+) B-lineage acute lymphoblastic leukemia. Using a principal component analysis, we found that robust MHC class II expression, coupled with appropriate costimulation, correlated with lower leukemic burden. We next assessed whether checkpoint blockade or therapeutic vaccination could improve survival in mice with pre-established leukemia. Consistent with the low mutation load in our leukemia model, we found that checkpoint blockade alone had only modest effects on survival. In contrast, robust heterologous vaccination with a peptide derived from the BCR-ABL fusion (BAp), a key driver mutation, generated a small population of mice that survived long-term. Checkpoint blockade strongly synergized with heterologous vaccination to enhance overall survival in mice with leukemia. Enhanced survival did not correlate with numbers of BAp:I-A(b)-specific T cells, but rather with increased expression of IL-10, IL-17, and granzyme B and decreased expression of programmed death 1 on these cells. Our findings demonstrate that vaccination to key driver mutations cooperates with checkpoint blockade and allows for immune control of cancers with low nonsynonymous mutation loads.


Assuntos
Pontos de Checagem do Ciclo Celular/fisiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Vacinação , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
14.
J Immunol ; 196(9): 3920-6, 2016 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-27001957

RESUMO

IL-15 regulates central and effector memory CD8 T cell (TCM and TEM, respectively) homeostatic proliferation, maintenance, and longevity. Consequently, IL-15 availability hypothetically defines the carrying capacity for total memory CD8 T cells within the host. In conflict with this hypothesis, previous observations demonstrated that boosting generates preternaturally abundant TEM that increases the total quantity of memory CD8 T cells in mice. In this article, we provide a potential mechanistic explanation by reporting that boosted circulating TEM do not require IL-15 for maintenance. We also investigated tissue-resident memory CD8 T cells (TRM), which protect nonlymphoid tissues from reinfection. We observed up to a 50-fold increase in the total magnitude of TRM in mouse mucosal tissues after boosting, suggesting that the memory T cell capacity in tissues is flexible and that TRM may not be under the same homeostatic regulation as primary central memory CD8 T cells and TEM Further analysis identified distinct TRM populations that depended on IL-15 for homeostatic proliferation and survival, depended on IL-15 for homeostatic proliferation but not for survival, or did not depend on IL-15 for either process. These observations on the numerical regulation of T cell memory indicate that there may be significant heterogeneity among distinct TRM populations and also argue against the common perception that developing vaccines that confer protection by establishing abundant TEM and TRM will necessarily erode immunity to previously encountered pathogens as the result of competition for IL-15.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Interleucina-15/metabolismo , Membrana Mucosa/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Proliferação de Células , Células Cultivadas , Citotoxicidade Imunológica , Homeostase , Imunização Secundária , Camundongos , Camundongos Endogâmicos C57BL , Vacinas Virais/imunologia
15.
Nat Immunol ; 17(3): 304-14, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26829766

RESUMO

The role of anergy, an acquired state of T cell functional unresponsiveness, in natural peripheral tolerance remains unclear. In this study, we found that anergy was selectively induced in fetal antigen-specific maternal CD4(+) T cells during pregnancy. A naturally occurring subpopulation of anergic polyclonal CD4(+) T cells, enriched for self antigen-specific T cell antigen receptors, was also present in healthy hosts. Neuropilin-1 expression in anergic conventional CD4(+) T cells was associated with hypomethylation of genes related to thymic regulatory T cells (Treg cells), and this correlated with their ability to differentiate into Foxp3(+) Treg cells that suppressed immunopathology. Thus, our data suggest that not only is anergy induction important in preventing autoimmunity but also it generates the precursors for peripheral Treg cell differentiation.


Assuntos
Autoimunidade/imunologia , Diferenciação Celular/imunologia , Anergia Clonal/imunologia , Histocompatibilidade Materno-Fetal/imunologia , Tolerância Periférica/imunologia , Células Precursoras de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Artrite Experimental/imunologia , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Citocinas/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Genes Codificadores da Cadeia alfa de Receptores de Linfócitos T , Immunoblotting , Masculino , Camundongos , Camundongos Knockout , Neuropilina-1/metabolismo , Gravidez , Receptores de Antígenos de Linfócitos T/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tolerância a Antígenos Próprios , Timócitos/imunologia
17.
PLoS Pathog ; 11(10): e1005177, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26485519

RESUMO

Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion.


Assuntos
Antígenos CD/imunologia , Apirase/imunologia , Biomarcadores , Linfócitos T CD8-Positivos/imunologia , Infecções por Vírus de RNA/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Infecções por Arenaviridae/imunologia , Cromatografia Líquida de Alta Pressão , Doença Crônica , Modelos Animais de Doenças , Citometria de Fluxo , Infecções por HIV/imunologia , Hepatite C Crônica/imunologia , Humanos , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos
18.
J Immunol ; 195(8): 4028-37, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26378075

RESUMO

BCR-ABL(+) acute lymphoblastic leukemia patients have transient responses to current therapies. However, the fusion of BCR to ABL generates a potential leukemia-specific Ag that could be a target for immunotherapy. We demonstrate that the immune system can limit BCR-ABL(+) leukemia progression although ultimately this immune response fails. To address how BCR-ABL(+) leukemia escapes immune surveillance, we developed a peptide: MHC class II tetramer that labels endogenous BCR-ABL-specific CD4(+) T cells. Naive mice harbored a small population of BCR-ABL-specific T cells that proliferated modestly upon immunization. The small number of naive BCR-ABL-specific T cells was due to negative selection in the thymus, which depleted BCR-ABL-specific T cells. Consistent with this observation, we saw that BCR-ABL-specific T cells were cross-reactive with an endogenous peptide derived from ABL. Despite this cross-reactivity, the remaining population of BCR-ABL reactive T cells proliferated upon immunization with the BCR-ABL fusion peptide and adjuvant. In response to BCR-ABL(+) leukemia, BCR-ABL-specific T cells proliferated and converted into regulatory T (Treg) cells, a process that was dependent on cross-reactivity with self-antigen, TGF-ß1, and MHC class II Ag presentation by leukemic cells. Treg cells were critical for leukemia progression in C57BL/6 mice, as transient Treg cell ablation led to extended survival of leukemic mice. Thus, BCR-ABL(+) leukemia actively suppresses antileukemia immune responses by converting cross-reactive leukemia-specific T cells into Treg cells.


Assuntos
Apresentação do Antígeno , Neoplasias Experimentais/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Linfócitos T Reguladores/imunologia , Animais , Reações Cruzadas , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/imunologia , Camundongos , Camundongos Knockout , Neoplasias Experimentais/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Linfócitos T Reguladores/patologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/imunologia
19.
J Exp Med ; 212(7): 1125-37, 2015 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-26034050

RESUMO

Programmed Death-1 (PD-1) has received considerable attention as a key regulator of CD8(+) T cell exhaustion during chronic infection and cancer because blockade of this pathway partially reverses T cell dysfunction. Although the PD-1 pathway is critical in regulating established "exhausted" CD8(+) T cells (TEX cells), it is unclear whether PD-1 directly causes T cell exhaustion. We show that PD-1 is not required for the induction of exhaustion in mice with chronic lymphocytic choriomeningitis virus (LCMV) infection. In fact, some aspects of exhaustion are more severe with genetic deletion of PD-1 from the onset of infection. Increased proliferation between days 8 and 14 postinfection is associated with subsequent decreased CD8(+) T cell survival and disruption of a critical proliferative hierarchy necessary to maintain exhausted populations long term. Ultimately, the absence of PD-1 leads to the accumulation of more cytotoxic, but terminally differentiated, CD8(+) TEX cells. These results demonstrate that CD8(+) T cell exhaustion can occur in the absence of PD-1. They also highlight a novel role for PD-1 in preserving TEX cell populations from overstimulation, excessive proliferation, and terminal differentiation.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Coriomeningite Linfocítica/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Transferência Adotiva , Animais , Bromodesoxiuridina , Diferenciação Celular/genética , Proliferação de Células/fisiologia , Citometria de Fluxo , Camundongos , Receptor de Morte Celular Programada 1/deficiência
20.
J Immunol ; 194(8): 3551-3555, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25769925

RESUMO

Programmed death-1 (PD-1) promotes T cell tolerance. Despite therapeutically targeting this pathway for chronic infections and tumors, little is known about how different T cell subsets are affected during blockade. We examined PD-1/PD ligand 1 (PD-L1) regulation of self-antigen-specific CD4 and CD8 T cells in autoimmune-susceptible models. PD-L1 blockade increased insulin-specific effector CD4 T cells in type 1 diabetes. However, anergic islet-specific CD4 T cells were resistant to PD-L1 blockade. Additionally, PD-L1 was critical for induction, but not maintenance, of CD8 T cell intestinal tolerance. PD-L1 blockade enhanced functionality of effector T cells, whereas established tolerant or anergic T cells were not dependent on PD-1/PD-L1 signaling to remain unresponsive. This highlights the existence of Ag-experienced T cell subsets that do not rely on PD-1/PD-L1 regulation. These findings illustrate how positive treatment outcomes and autoimmunity development during PD-1/PD-L1 inhibition are linked to the differentiation state of a T cell.


Assuntos
Doenças Autoimunes/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Anergia Clonal , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/imunologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Modelos Animais de Doenças , Suscetibilidade a Doenças/imunologia , Suscetibilidade a Doenças/patologia , Feminino , Tolerância Imunológica/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Receptor de Morte Celular Programada 1/genética , Transdução de Sinais/genética
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