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1.
Cancer Immunol Res ; 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674357

RESUMO

Antibody-mediated transient depletion of CD4+ cells enhances the expansion of tumor-reactive CD8+ T cells and exhibits robust antitumor effects in preclinical and clinical studies. To investigate the clonal T-cell responses following transient CD4+ cell depletion in patients with cancer, we conducted a temporal analysis of the T-cell receptor (TCR) repertoire in the first-in-human clinical trial of IT1208, a defucosylated humanized monoclonal anti-CD4. Transient depletion of CD4+ cells promoted replacement of T-cell clones among CD4+ and CD8+ T cells in the blood. This replacement of the TCR repertoire was associated with the extent of CD4+ T-cell depletion and an increase in CD8+ T-cell count in the blood. Next, we focused on T-cell clones overlapping between the blood and tumor in order to track tumor-associated T-cell clones in the blood. The total frequency of blood-tumor overlapping clones tended to increase in patients receiving a depleting dose of anti-CD4, which was accompanied by the replacement of overlapping clones. The greater expansion of CD8+ overlapping clones was commonly observed in the patients who achieved tumor shrinkage. These results suggested that the clonal replacement of the TCR repertoire induced by transient CD4+ cell depletion was accompanied by the expansion of tumor-reactive T-cell clones that mediated antitumor responses. Our findings propose beneficial remodeling of the TCR repertoire following transient CD4+ cell depletion and provide novel insight into the antitumor effects of monoclonal anti-CD4 treatment in patients with cancer.

2.
Cell ; 184(5): 1262-1280.e22, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33636129

RESUMO

Improving effector activity of antigen-specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (TEFF)-driving transcription factors (TFs), the transcriptional coordination of TEFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a key mechanism restraining TEFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced TEFF responses without compromising memory or exhaustion precursors. Fli1 restrained TEFF lineage differentiation by binding to cis-regulatory elements of effector-associated genes. Loss of Fli1 increased chromatin accessibility at ETS:RUNX motifs, allowing more efficient Runx3-driven TEFF biology. CD8+ T cells lacking Fli1 provided substantially better protection against multiple infections and tumors. These data indicate that Fli1 safeguards the developing CD8+ T cell transcriptional landscape from excessive ETS:RUNX-driven TEFF cell differentiation. Moreover, genetic deletion of Fli1 improves TEFF differentiation and protective immunity in infections and cancer.

3.
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.

4.
Sci Rep ; 10(1): 20763, 2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33247161

RESUMO

Hepatitis B virus (HBV) is the major causative factor of chronic viral hepatitis, liver cirrhosis, and hepatocellular carcinoma. We previously demonstrated that a proinflammatory cytokine IL-1ß reduced the level of HBV RNA. However, the mechanism underlying IL-1ß-mediated viral RNA reduction remains incompletely understood. In this study, we report that immune regulator Monocyte chemotactic protein-1-induced protein 1 (MCPIP1) can reduce HBV RNA in hepatocytes. MCPIP1 expression level was higher in the liver tissue of HBV-infected patients and mice. Overexpression of MCPIP1 decreased HBV RNA, whereas ablating MCPIP1 in vitro enhanced HBV production. The domains responsible for RNase activity or oligomerization, were required for MCPIP1-mediated viral RNA reduction. The epsilon structure of HBV RNA was important for its antiviral activity and cleaved by MCPIP1 in the cell-free system. Lastly, knocking out MCPIP1 attenuated the anti-HBV effect of IL-1ß, suggesting that MCPIP1 is required for IL-1ß-mediated HBV RNA reduction. Overall, these results suggest that MCPIP1 may be involved in the antiviral effect downstream of IL-1ß.

5.
Immunity ; 52(5): 825-841.e8, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32396847

RESUMO

CD8+ T cell exhaustion is a major barrier to current anti-cancer immunotherapies. Despite this, the developmental biology of exhausted CD8+ T cells (Tex) remains poorly defined, restraining improvement of strategies aimed at "re-invigorating" Tex cells. Here, we defined a four-cell-stage developmental framework for Tex cells. Two TCF1+ progenitor subsets were identified, one tissue restricted and quiescent and one more blood accessible, that gradually lost TCF1 as it divided and converted to a third intermediate Tex subset. This intermediate subset re-engaged some effector biology and increased upon PD-L1 blockade but ultimately converted into a fourth, terminally exhausted subset. By using transcriptional and epigenetic analyses, we identified the control mechanisms underlying subset transitions and defined a key interplay between TCF1, T-bet, and Tox in the process. These data reveal a four-stage developmental hierarchy for Tex cells and define the molecular, transcriptional, and epigenetic mechanisms that could provide opportunities to improve cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Epigênese Genética/imunologia , Neoplasias/imunologia , Subpopulações de Linfócitos T/imunologia , Transcrição Genética/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Epigênese Genética/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/imunologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/imunologia , Humanos , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Neoplasias/genética , Neoplasias/terapia , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Subpopulações de Linfócitos T/metabolismo , Transcrição Genética/genética
6.
J Exp Med ; 217(5)2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32150623

RESUMO

In chronic infections, the immune response fails to control virus, leading to persistent antigen stimulation and the progressive development of T cell exhaustion. T cell effector differentiation is poorly understood in the context of exhaustion, but targeting effector programs may provide new strategies for reinvigorating T cell function. We identified Tribbles pseudokinase 1 (Trib1) as a central regulator of antiviral T cell immunity, where loss of Trib1 led to a sustained enrichment of effector-like KLRG1+ T cells, enhanced function, and improved viral control. Single-cell profiling revealed that Trib1 restrains a population of KLRG1+ effector CD8 T cells that is transcriptionally distinct from exhausted cells. Mechanistically, we identified an interaction between Trib1 and the T cell receptor (TCR) signaling activator, MALT1, which disrupted MALT1 signaling complexes. These data identify Trib1 as a negative regulator of TCR signaling and downstream function, and reveal a link between Trib1 and effector versus exhausted T cell differentiation that can be targeted to improve antiviral immunity.

7.
Immunity ; 51(5): 840-855.e5, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31606264

RESUMO

TCF-1 is a key transcription factor in progenitor exhausted CD8 T cells (Tex). Moreover, this Tex cell subset mediates responses to PD-1 checkpoint pathway blockade. However, the role of the transcription factor TCF-1 in early fate decisions and initial generation of Tex cells is unclear. Single-cell RNA sequencing (scRNA-seq) and lineage tracing identified a TCF-1+Ly108+PD-1+ CD8 T cell population that seeds development of mature Tex cells early during chronic infection. TCF-1 mediated the bifurcation between divergent fates, repressing development of terminal KLRG1Hi effectors while fostering KLRG1Lo Tex precursor cells, and PD-1 stabilized this TCF-1+ Tex precursor cell pool. TCF-1 mediated a T-bet-to-Eomes transcription factor transition in Tex precursors by promoting Eomes expression and drove c-Myb expression that controlled Bcl-2 and survival. These data define a role for TCF-1 in early-fate-bifurcation-driving Tex precursor cells and also identify PD-1 as a protector of this early TCF-1 subset.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Redes Reguladoras de Genes , Fator 1 de Transcrição de Linfócitos T/metabolismo , Transcrição Genética , Animais , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Doença Crônica , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Camundongos , Receptor de Morte Celular Programada 1/metabolismo , Fator 1 de Transcrição de Linfócitos T/genética , Viroses/genética , Viroses/imunologia , Viroses/virologia
9.
J Exp Med ; 216(12): 2748-2762, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31558615

RESUMO

Resident memory T cells (TRM cells) are an important first-line defense against respiratory pathogens, but the unique contributions of lung TRM cell populations to protective immunity and the factors that govern their localization to different compartments of the lung are not well understood. Here, we show that airway and interstitial TRM cells have distinct effector functions and that CXCR6 controls the partitioning of TRM cells within the lung by recruiting CD8 TRM cells to the airways. The absence of CXCR6 significantly decreases airway CD8 TRM cells due to altered trafficking of CXCR6-/- cells within the lung, and not decreased survival in the airways. CXCL16, the ligand for CXCR6, is localized primarily at the respiratory epithelium, and mice lacking CXCL16 also had decreased CD8 TRM cells in the airways. Finally, blocking CXCL16 inhibited the steady-state maintenance of airway TRM cells. Thus, the CXCR6/CXCL16 signaling axis controls the localization of TRM cells to different compartments of the lung and maintains airway TRM cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Memória Imunológica , Imunomodulação , Receptores CXCR6/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Animais , Expressão Gênica , Humanos , Imunofenotipagem , Camundongos , Camundongos Knockout , Ligação Proteica , Receptores CXCR6/genética , Especificidade do Receptor de Antígeno de Linfócitos T
10.
Biochem Biophys Res Commun ; 518(1): 26-31, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31400856

RESUMO

Some APOBEC3 family members have antiviral activity against retroviruses and DNA viruses. Hepatitis B virus (HBV) is a DNA virus that is the major causative factor of severe liver diseases such as cirrhosis and hepatocellular carcinoma. To determine whether APOBEC3 variants in humans have different anti-HBV activities, we evaluated natural variants of APOBEC3C, APOBEC3G, and APOBEC3H using an HBV-replicating cell culture model. Our data demonstrate that the APOBEC3C variant S188I had increased restriction activity and hypermutation frequency against HBV DNA. In contrast, the APOBEC3G variant H186R did not alter the anti-HBV and hypermutation activities. Among APOBEC3H polymorphisms (hap I-VII) and splicing variants (SV-200, SV-183, SV-182, and SV-154), hap II SV-183 showed the strongest restriction activity. These data suggest that the genetic variations in APOBEC3 genes may affect the efficiency of HBV elimination in humans.


Assuntos
Desaminase APOBEC-3G/genética , Aminoidrolases/genética , Antivirais/metabolismo , Citidina Desaminase/genética , Variação Genética , Vírus da Hepatite B/fisiologia , Desaminase APOBEC-3G/metabolismo , Aminoidrolases/metabolismo , Linhagem Celular Tumoral , Citidina Desaminase/metabolismo , DNA Viral/genética , Regulação da Expressão Gênica , Humanos , Hipermutação Somática de Imunoglobulina/genética , Replicação Viral
11.
Semin Immunopathol ; 41(3): 327-337, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30989321

RESUMO

CD8+ T cells are important for the protective immunity against intracellular pathogens and tumor. In the case of chronic infection or cancer, CD8+ T cells are exposed to persistent antigen and/or inflammatory signals. This excessive amount of signals often leads CD8+ T cells to gradual deterioration of T cell function, a state called "exhaustion." Exhausted T cells are characterized by progressive loss of effector functions (cytokine production and killing function), expression of multiple inhibitory receptors (such as PD-1 and LAG3), dysregulated metabolism, poor memory recall response, and homeostatic proliferation. These altered functions are closely related with altered transcriptional program and epigenetic landscape that clearly distinguish exhausted T cells from normal effector and memory T cells. T cell exhaustion is often associated with inefficient control of persisting infections and cancers, but re-invigoration of exhausted T cells with inhibitory receptor blockade can promote improved immunity and disease outcome. Accumulating evidences support the therapeutic potential of targeting exhausted T cells. However, exhausted T cells comprise heterogenous cell population with distinct responsiveness to intervention. Understanding molecular mechanism of T cell exhaustion is essential to establish rational immunotherapeutic interventions.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Suscetibilidade a Doenças , Imunomodulação , Animais , Antígenos/imunologia , Suscetibilidade a Doenças/imunologia , Regulação da Expressão Gênica , Humanos , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
12.
Cell Rep ; 23(7): 2142-2156, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29768211

RESUMO

Persistent viral infections and tumors drive development of exhausted T (TEX) cells. In these settings, TEX cells establish an important host-pathogen or host-tumor stalemate. However, TEX cells erode over time, leading to loss of pathogen or cancer containment. We identified microRNA (miR)-155 as a key regulator of sustained TEX cell responses during chronic lymphocytic choriomeningitis virus (LCMV) infection. Genetic deficiency of miR-155 ablated CD8 T cell responses during chronic infection. Conversely, enhanced miR-155 expression promoted expansion and long-term persistence of TEX cells. However, rather than strictly antagonizing exhaustion, miR-155 promoted a terminal TEX cell subset. Transcriptional profiling identified coordinated control of cell signaling and transcription factor pathways, including the key AP-1 family member Fosl2. Overexpression of Fosl2 reversed the miR-155 effects, identifying a link between miR-155 and the AP-1 transcriptional program in regulating TEX cells. Thus, we identify a mechanism of miR-155 regulation of TEX cells and a key role for Fosl2 in T cell exhaustion.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Doenças Transmissíveis/genética , Doenças Transmissíveis/imunologia , MicroRNAs/metabolismo , Animais , Diferenciação Celular , Proliferação de Células/genética , Doença Crônica , Doenças Transmissíveis/patologia , Antígeno 2 Relacionado a Fos/metabolismo , Regulação da Expressão Gênica , Subpopulações de Linfócitos/imunologia , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Fenótipo , Fatores de Tempo , Fator de Transcrição AP-1/metabolismo , Transcrição Genética
13.
Int Immunol ; 30(4): 141-154, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29617862

RESUMO

Immunotherapies have led to the successful development of novel therapies for cancer. However, there is increasing concern regarding the adverse effects caused by non-tumor-specific immune responses. Here, we report an effective strategy to generate high-avidity tumor-antigen-specific CTLs, using Cas9/single-guide RNA (sgRNA) ribonucleoprotein (RNP) delivery. As a proof-of-principle demonstration, we selected the gp100 melanoma-associated tumor antigen, and cloned the gp100-specific high-avidity TCR from gp100-immunized mice. To enable rapid structural dissection of the TCR, we developed a 3D protein structure modeling system for the TCR/antigen-major histocompatibility complex (pMHC) interaction. Combining these technologies, we efficiently generated gp100-specific PD-1(-) CD8+ T cells, and demonstrated that the genetically engineered CD8+ T cells have high avidity against melanoma cells both in vitro and in vivo. Our methodology offers computational prediction of the TCR response, and enables efficient generation of tumor antigen-specific CD8+ T cells that can neutralize tumor-induced immune suppression leading to a potentially powerful cancer therapeutic.


Assuntos
Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Sistemas CRISPR-Cas , Edição de Genes , Neoplasias/genética , Neoplasias/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia , Animais , Antígenos de Neoplasias/química , Linhagem Celular Tumoral , Feminino , Técnicas de Inativação de Genes , Genes Reporter , Melanoma Experimental , Camundongos , Modelos Moleculares , Complexos Multiproteicos , Neoplasias/metabolismo , Peptídeos/química , Peptídeos/imunologia , Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica , Multimerização Proteica , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Antígeno gp100 de Melanoma/química , Antígeno gp100 de Melanoma/imunologia , Antígeno gp100 de Melanoma/metabolismo
14.
Immunity ; 48(2): 243-257.e10, 2018 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-29466756

RESUMO

T cell development is orchestrated by transcription factors that regulate the expression of genes initially buried within inaccessible chromatin, but the transcription factors that establish the regulatory landscape of the T cell lineage remain unknown. Profiling chromatin accessibility at eight stages of T cell development revealed the selective enrichment of TCF-1 at genomic regions that became accessible at the earliest stages of development. TCF-1 was further required for the accessibility of these regulatory elements and at the single-cell level, it dictated a coordinate opening of chromatin in T cells. TCF-1 expression in fibroblasts generated de novo chromatin accessibility even at chromatin regions with repressive marks, inducing the expression of T cell-restricted genes. These results indicate that a mechanism by which TCF-1 controls T cell fate is through its widespread ability to target silent chromatin and establish the epigenetic identity of T cells.


Assuntos
Linhagem da Célula , Epigenômica , Fator 1-alfa Nuclear de Hepatócito/fisiologia , Fator 1 de Transcrição de Linfócitos T/fisiologia , Linfócitos T/fisiologia , Animais , Cromatina/fisiologia , Montagem e Desmontagem da Cromatina , Fibroblastos/metabolismo , Camundongos , Células NIH 3T3 , Transcrição Genética
15.
Cell Rep ; 20(11): 2584-2597, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-28903040

RESUMO

MicroRNAs play an important role in T cell responses. However, how microRNAs regulate CD8 T cell memory remains poorly defined. Here, we found that miR-150 negatively regulates CD8 T cell memory in vivo. Genetic deletion of miR-150 disrupted the balance between memory precursor and terminal effector CD8 T cells following acute viral infection. Moreover, miR-150-deficient memory CD8 T cells were more protective upon rechallenge. A key circuit whereby miR-150 repressed memory CD8 T cell development through the transcription factor c-Myb was identified. Without miR-150, c-Myb was upregulated and anti-apoptotic targets of c-Myb, such as Bcl-2 and Bcl-xL, were also increased, suggesting a miR-150-c-Myb survival circuit during memory CD8 T cell development. Indeed, overexpression of non-repressible c-Myb rescued the memory CD8 T cell defects caused by overexpression of miR-150. Overall, these results identify a key role for miR-150 in memory CD8 T cells through a c-Myb-controlled enhanced survival circuit.


Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Memória Imunológica , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-myb/metabolismo , Animais , Apoptose/genética , Feminino , Imunidade , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética
16.
Nat Protoc ; 12(9): 1980-1998, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28858287

RESUMO

Retroviral (RV) expression of genes of interest (GOIs) is an invaluable tool and has formed the foundation of cellular engineering for adoptive cell therapy in cancer and other diseases. However, monitoring of transduced T cells long term (weeks to months) in vivo remains challenging because of the low frequency and often poor durability of transduced T cells over time when transferred without enrichment. Traditional methods often require additional overnight in vitro culture after transduction. Moreover, in vitro-generated effector CD8+ T cells enriched by sorting often have reduced viability, making it difficult to monitor the fate of transferred cells in vivo. Here, we describe an optimized mouse CD8+ T-cell RV transduction protocol that uses simple and rapid Percoll density centrifugation to enrich RV-susceptible activated CD8+ T cells. Percoll density centrifugation is simple, can be done on the day of transduction, requires minimal time, has low reagent costs and improves cell recovery (up to 60%), as well as the frequency of RV-transduced cells (∼sixfold over several weeks in vivo as compared with traditional methods). We have used this protocol to assess the long-term stability of CD8+ T cells after RV transduction by comparing the durability of T cells transduced with retroviruses expressing each of six commonly used RV reporter genes. Thus, we provide an optimized enrichment and transduction approach that allows long-term in vivo assessment of RV-transduced T cells. The overall procedure from T-cell isolation to RV transduction takes 2 d, and enrichment of activated T cells can be done in 1 h.


Assuntos
Linfócitos T CD8-Positivos/virologia , Vetores Genéticos/genética , Retroviridae/genética , Transdução Genética/métodos , Animais , Camundongos
17.
Immunity ; 47(3): 435-449.e8, 2017 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-28930659

RESUMO

Commitment to the innate lymphoid cell (ILC) lineage is determined by Id2, a transcriptional regulator that antagonizes T and B cell-specific gene expression programs. Yet how Id2 expression is regulated in each ILC subset remains poorly understood. We identified a cis-regulatory element demarcated by a long non-coding RNA (lncRNA) that controls the function and lineage identity of group 1 ILCs, while being dispensable for early ILC development and homeostasis of ILC2s and ILC3s. The locus encoding this lncRNA, which we termed Rroid, directly interacted with the promoter of its neighboring gene, Id2, in group 1 ILCs. Moreover, the Rroid locus, but not the lncRNA itself, controlled the identity and function of ILC1s by promoting chromatin accessibility and deposition of STAT5 at the promoter of Id2 in response to interleukin (IL)-15. Thus, non-coding elements responsive to extracellular cues unique to each ILC subset represent a key regulatory layer for controlling the identity and function of ILCs.


Assuntos
Regulação da Expressão Gênica , Imunidade Inata/genética , Linfócitos/metabolismo , RNA Longo não Codificante/genética , Sequências Reguladoras de Ácido Nucleico , Animais , Diferenciação Celular , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Montagem e Desmontagem da Cromatina , Feminino , Perfilação da Expressão Gênica , Loci Gênicos , Homeostase , Proteína 2 Inibidora de Diferenciação/genética , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Linfócitos/imunologia , Masculino , Camundongos , Regiões Promotoras Genéticas , Fator de Transcrição STAT5/metabolismo , Transcrição Genética
18.
Front Immunol ; 8: 1842, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29326717

RESUMO

Chronic graft-versus-host disease (cGVHD) is a major complication in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Graft-derived T cells (TG) have been implicated in the induction of cGVHD; however, the extent of their contribution to the pathogenesis of cGVHD remains unclear. Using a mouse model of cGVHD, we demonstrate that TG predominate over hematopoietic stem cell-derived T cells generated de novo (THSC) in cGVHD-affected organs such as the liver and lung even at day 63 after allo-HSCT. Persisting TG, in particular CD8+ TG, not only displayed an exhausted or senescent phenotype but also contained a substantial proportion of cells that had the potential to proliferate and produce inflammatory cytokines. Host antigens indirectly presented by donor HSC-derived hematopoietic cells were involved in the maintenance of TG in the reconstituted host. Selective depletion of TG in the chronic phase of disease resulted in the expansion of THSC and thus neither the survival nor histopathology of cGVHD was ameliorated. On the other hand, THSC depletion caused activation of TG and resulted in a lethal TG-mediated exacerbation of GVHD. The findings presented here clarify the pathological role of long-lasting TG in cGVHD.

19.
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
20.
Science ; 354(6316): 1165-1169, 2016 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-27789799

RESUMO

Exhausted T cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (PD-1). However, the regulation of gene expression in exhausted T cells is poorly understood. Here, we define the accessible chromatin landscape in exhausted CD8+ T cells and show that it is distinct from functional memory CD8+ T cells. Exhausted CD8+ T cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers. Genome editing shows that PD-1 expression is regulated in part by an exhaustion-specific enhancer that contains essential RAR, T-bet, and Sox3 motifs. Functional enhancer maps may offer targets for genome editing that alter gene expression preferentially in exhausted CD8+ T cells.


Assuntos
Antígeno B7-H1/genética , Linfócitos T CD8-Positivos/imunologia , Elementos Facilitadores Genéticos , Epigênese Genética , Memória Imunológica/genética , Animais , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/transplante , Linhagem da Célula/genética , Cromatina/imunologia , Doença Crônica , Modelos Animais de Doenças , Edição de Genes , Infecções por HIV/terapia , Hepatite C Crônica/terapia , Humanos , Imunoterapia , Coriomeningite Linfocítica/terapia , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição SOXB1/metabolismo , Proteínas com Domínio T/metabolismo , Transcrição Genética
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