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1.
Nat Immunol ; 17(12): 1467-1478, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27776108

RESUMO

Tissue-resident memory T cells (TRM cells) in the airways mediate protection against respiratory infection. We characterized TRM cells expressing integrin αE (CD103) that reside within the epithelial barrier of human lungs. These cells had specialized profiles of chemokine receptors and adhesion molecules, consistent with their unique localization. Lung TRM cells were poised for rapid responsiveness by constitutive expression of deployment-ready mRNA encoding effector molecules, but they also expressed many inhibitory regulators, suggestive of programmed restraint. A distinct set of transcription factors was active in CD103+ TRM cells, including Notch. Genetic and pharmacological experiments with mice revealed that Notch activity was required for the maintenance of CD103+ TRM cells. We have thus identified specialized programs underlying the residence, persistence, vigilance and tight control of human lung TRM cells.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Memória Imunológica , Vírus da Influenza A Subtipo H3N2/imunologia , Pulmão/imunologia , Infecções por Orthomyxoviridae/imunologia , Receptor Notch1/metabolismo , Receptor Notch2/metabolismo , Infecções Respiratórias/imunologia , Animais , Antígenos CD/metabolismo , Células Cultivadas , Feminino , Humanos , Cadeias alfa de Integrinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Receptor Notch1/genética , Receptor Notch2/genética
2.
Nat Immunol ; 15(12): 1143-51, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25344724

RESUMO

Activated CD8(+) T cells choose between terminal effector cell (TEC) or memory precursor cell (MPC) fates. We found that the signaling receptor Notch controls this 'choice'. Notch promoted the differentiation of immediately protective TECs and was correspondingly required for the clearance of acute infection with influenza virus. Notch activated a major portion of the TEC-specific gene-expression program and suppressed the MPC-specific program. Expression of Notch was induced on naive CD8(+) T cells by inflammatory mediators and interleukin 2 (IL-2) via pathways dependent on the metabolic checkpoint kinase mTOR and the transcription factor T-bet. These pathways were subsequently amplified downstream of Notch, creating a positive feedback loop. Notch thus functions as a central hub where information from different sources converges to match effector T cell differentiation to the demands of an infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Receptores Notch/imunologia , Subpopulações de Linfócitos T/imunologia , Imunidade Adaptativa/imunologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/citologia , Separação Celular , Citometria de Fluxo , Vírus da Influenza A , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Infecções por Orthomyxoviridae/imunologia , Reação em Cadeia da Polimerase em Tempo Real , Subpopulações de Linfócitos T/citologia , Transcriptoma , Transdução Genética
4.
Immunity ; 43(5): 831-3, 2015 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-26588772

RESUMO

The Notch pathway is an attractive therapeutic target for treatment of cancer and T cell-mediated pathology, but Notch inhibition leads to many side effects. Pinnell et al. (2015) demonstrate that oncogenic functions can be separated biochemically from other functions of Notch, opening new options for more selective targeting of this pathway.


Assuntos
Leucemia/metabolismo , Proteínas Inibidoras de STAT Ativados/metabolismo , Receptor Notch1/metabolismo , Linfócitos T/metabolismo , Fatores de Transcrição/metabolismo , Animais , Humanos
5.
Trends Immunol ; 36(12): 802-814, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26617322

RESUMO

Differentiation of naïve T cells into effector cells is required for optimal protection against different classes of microbial pathogen and for the development of immune memory. Recent findings have revealed important roles for the Notch signaling pathway in T cell differentiation into all known effector subsets, raising the question of how this pathway controls such diverse differentiation programs. Studies in preclinical models support the therapeutic potential of manipulating the Notch pathway to alleviate immune pathology, highlighting the importance of understanding the mechanisms through which Notch regulates T cell differentiation and function. We review these findings here, and outline both unifying principles involved in Notch-mediated T cell fate decisions and cell type- and context-specific differences that may present the most suitable points for therapeutic intervention.


Assuntos
Diferenciação Celular/imunologia , Receptores Notch/imunologia , Linfócitos T/imunologia , Animais , Humanos , Ativação Linfocitária/imunologia , Transdução de Sinais/imunologia
6.
Proc Natl Acad Sci U S A ; 109(23): 9041-6, 2012 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-22615412

RESUMO

Generation of effective immune responses requires expansion of rare antigen-specific CD4(+) T cells. The magnitude of the responding population is ultimately determined by proliferation and survival. Both processes are tightly controlled to limit responses to innocuous antigens. Sustained expansion occurs only when innate immune sensors are activated by microbial stimuli or by adjuvants, which has important implications for vaccination. The molecular identity of the signals controlling sustained T-cell responses is not fully clear. Here, we describe a prominent role for the Notch pathway in this process. Coactivation of Notch allows accumulation of far greater numbers of activated CD4(+) T cells than stimulation via T-cell receptor and classic costimulation alone. Notch does not overtly affect cell cycle entry or progression of CD4(+) T cells. Instead, Notch protects activated CD4(+) T cells against apoptosis after an initial phase of clonal expansion. Notch induces a broad antiapoptotic gene expression program that protects against intrinsic, as well as extrinsic, apoptosis pathways. Both Notch1 and Notch2 receptors and the canonical effector RBPJ (recombination signal binding protein for immunoglobulin kappa J region) are involved in this process. Correspondingly, CD4(+) T-cell responses to immunization with protein antigen are strongly reduced in mice lacking these components of the Notch pathway. Our findings, therefore, show that Notch controls the magnitude of CD4(+) T-cell responses by promoting cellular longevity.


Assuntos
Apoptose/imunologia , Receptores Notch/metabolismo , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Apoptose/genética , Sobrevivência Celular/imunologia , Sobrevivência Celular/fisiologia , Citometria de Fluxo , Hemocianinas , Imunização , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries , Reação em Cadeia da Polimerase em Tempo Real , Receptores Notch/genética
7.
Adv Exp Med Biol ; 785: 107-20, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23456843

RESUMO

A fundamental property of the adaptive immune system is the ability to generate antigen-specific memory, which protects against repeated infections with the same pathogens and determines the success of vaccination. Immune memory is built up alongside a response providing direct protection during the course of a primary immune response. For CD8 T cells, this involves the generation of two distinct types of effector cells. Short lived effector cells (SLECs) confer immediate protection, but contribute little to the memory repertoire. Memory precursor effector cells (MPECs) have the ability to respond to survival signals and develop into memory cells. These two types of cells can be distinguished on the basis of surface markers and express distinct genetic programs. A single naive CD8 T cell can give rise to both MPEC and SLEC daughter cells. This may involve an initial asymmetric division or depend on later instructive signals acting on equipotent daughter cells. Strong inflammatory signals favor the generation of SLECs and weaker inflammation favors the generation of MPECs. A distinguishing feature of MPECs is their ability to persist when most effector cells die. This survival depends on signals from the IL-7 receptor, which induce expression of anti-apoptotic factors. MPECs are therefore characterized by expression of the IL-7 receptor as well as the CCR7 chemokine receptor, which allows homing to areas in lymphoid organs where IL-7 is produced. Critical for persistence of MPECs is further their responsiveness to myeloid cell derived IL-15, which instructs these cells to switch their metabolic programs from glycolysis associated with rapid proliferation to fatty acid oxidation required during a more resting state. As the mechanisms determining generation of immunological memory are unraveled, opportunities will emerge for the improvement of vaccination strategies.


Assuntos
Imunidade Adaptativa , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Memória Imunológica , Células Precursoras de Linfócitos T/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Sobrevivência Celular , Expressão Gênica , Humanos , Interleucina-15/genética , Interleucina-15/imunologia , Camundongos , Células Precursoras de Linfócitos T/citologia , Células Precursoras de Linfócitos T/metabolismo , Receptores CCR7/genética , Receptores CCR7/imunologia , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/imunologia , Transdução de Sinais , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo
8.
Adv Immunol ; 137: 43-82, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29455847

RESUMO

CD8+ T cells clear primary infections with intracellular pathogens and provide long-term immunity against reinfection. Two different types of CD8+ T cells are responsible for these functions: short-lived effector T cells and memory T cells. The cellular relationship between these two types of CD8+ T cells has been subject to much investigation. Both cell types can derive from a single naïve CD8+ T cell precursor. Their generation requires a fate choice early during a T cell response. As a result, two populations of T cells emerge. One of these consists of terminally differentiated short-lived effector T cells. The other contains cells able to develop into long-lived memory T cells. A foundation for development of these two populations may be laid during the first division of an activated naïve T cell precursor, as a consequence of asymmetric segregation of fate-determining factors into the daughter cells. Nonetheless, the binary choice between the two lineages is strongly influenced by signals, which ensure that the differentiation process is matched with the needs posed by the infection. Here, we will discuss the genetic and metabolic programs governing differentiation of these two lineages as well as the processes leading to their induction and consolidation to create bistability. These processes involve extensive lateral inhibition between the programs as well as positive feedback between the genetic programs and the signaling pathways responsible for their induction. These features will be highlighted by discussing the role of the Notch signaling pathway in guiding the decision between the two lineages.


Assuntos
Diferenciação Celular , Homeostase , Memória Imunológica , Subpopulações de Linfócitos T/fisiologia , Linfócitos T/fisiologia , Animais , Linhagem da Célula , Retroalimentação Fisiológica , Humanos , Imunidade Celular , Transdução de Sinais
9.
Front Immunol ; 4: 334, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24155745

RESUMO

Innate lymphoid cells (ILCs) are emerging key players of the immune system with close lineage relationship to T cells. ILC2 play an important role in protective immunity against multicellular parasites, but are also involved in the pathogenesis of type 2 immune diseases. Here, we have studied the developmental requirements for human ILC2. We report that ILC2 are present in the thymus of young human donors, possibly reflecting local differentiation. Furthermore, we show that uncommitted lineage(-)CD34(+)CD1a(-)human thymic progenitors have the capacity to develop into ILC2 in vitro under the influence of Notch signaling, either by stimulation with the Notch ligand Delta like 1 (Dll1) or by expression of the active intracellular domain of NOTCH1 (NICD1). The capacity of NICD1 to mobilize the ILC2 differentiation program was sufficiently potent to override commitment to the T cell lineage in CD34(+)CD1a(+) progenitors and force them into the ILC2 lineage. As Notch is an important factor also for T cell development, these results raise the question how one and the same signaling pathway can elicit such distinct developmental outcomes from the same precursors. We provide evidence that Notch signal strength is a critical determinant in this decision: by tuning signal amplitude, Notch can be converted from a T cell inducer (low signal strength) to an ILC2 inducer (high signal strength). Thus, this study enhances our understanding of human ILC2 development and identifies a mechanism determining specificity of Notch signal output during T cell and ILC2 differentiation.

10.
Eur J Immunol ; 37(3): 807-17, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17304625

RESUMO

In Th1 and Th2 memory lymphocytes, the genes for the cytokines interleukin (IL)-4 and interferon-gamma (IFN-gamma) are imprinted for expression upon restimulation. This cytokine memory is based on expression of the transcription factors T-bet for IFN-gamma, and GATA-3 for IL-4, and epigenetic modification of the cytokine genes. In Th2 cells, expression of the cytokine IL-10 is also induced by GATA-3. Here, we show that this induction is initially not accompanied by epigenetic modification of the IL-10 gene. Only after repeated restimulation of a memory Th2 cell in the presence of IL-4, extensive histone acetylation of the IL-10 gene is detectable. This epigenetic imprinting correlates with the development of a memory for IL-10 in repeatedly restimulated Th2 cells. In Th1 cells, IL-10 expression is induced by IL-12, but the IL-10 gene lacks detectable histone acetylation. Accordingly, IL-10 expression in restimulated memory Th1 cells remains conditional on the presence of IL-12. This finding defines a potential anti-inflammatory role for IL-12 in Th1 recall responses. While in primary Th1 responses IL-12 is required to induce expression of the pro-inflammatory cytokine IFN-gamma, in secondary Th1 responses IFN-gamma re-expression is independent of IL-12, which still is able to induce expression of the anti-inflammatory cytokine IL-10.


Assuntos
Fator de Transcrição GATA3/fisiologia , Impressão Genômica/imunologia , Memória Imunológica , Interleucina-10/biossíntese , Interleucina-12/fisiologia , Interleucina-4/fisiologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Células Cultivadas , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Memória Imunológica/genética , Interleucina-10/genética , Interleucina-10/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Regiões Promotoras Genéticas/imunologia , Ligação Proteica/genética , Ligação Proteica/imunologia , Células Th1/metabolismo
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