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1.
Artigo em Inglês | MEDLINE | ID: mdl-33558365

RESUMO

Heightened immunity after a primary infection, persistent control of low-level infection, or vanquished immunity from chronic-active infection and cancer are interrelated issues concerning the nature of T-cell regeneration during immunity. For many regenerating tissues and cellular systems, such as epithelia and blood, there are at least three distinguishable stages of development and repair, marked by progressive loss of self-renewal and progressive commitment to differentiation. T cells seem to be no different. Quiescent precursors become activated and yield anabolic, proliferative progenitors while self-renewing the quiescent precursor population. Activated progenitors then yield differentiated cellular descendants alongside the self-renewal of progenitors. Nomenclature reflecting the mutually opposing nature of T-cell self-renewal and T-cell differentiation would help synchronize phenomena such as T-cell memory, protective immunity, and T-cell exhaustion with other regenerative paradigms, as well as offer new strategies to influence the intensity and duration of immunity.

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.
JCI Insight ; 3(22)2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30429372

RESUMO

Tissue-resident memory T cells (TRMs) accelerate pathogen clearance through rapid and enhanced functional responses in situ. TRMs are prevalent in diverse anatomic sites throughout the human lifespan, yet their phenotypic and functional diversity has not been fully described. Here, we identify subpopulations of human TRMs based on the ability to efflux fluorescent dyes [efflux(+) TRMs] located within mucosal and lymphoid sites with distinct transcriptional profiles, turnover, and functional capacities. Compared with efflux(-) TRMs, efflux(+) TRMs showed transcriptional and phenotypic features of quiescence including reduced turnover, decreased expression of exhaustion markers, and increased proliferative capacity and signaling in response to homeostatic cytokines. Moreover, upon activation, efflux(+) TRMs secreted lower levels of inflammatory cytokines such as IFN-γ and IL-2 and underwent reduced degranulation. Interestingly, analysis of TRM subsets following activation revealed that both efflux(+) and efflux(-) TRMs undergo extensive transcriptional changes following TCR ligation but retain core TRM transcriptional properties including retention markers, suggesting that TRMs carry out effector function in situ. Overall, our results suggest a model for tissue-resident immunity wherein heterogeneous subsets have differential capacities for longevity and effector function.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Corantes Fluorescentes , Humanos , Tecido Linfoide/citologia , Mitocôndrias/metabolismo , Modelos Imunológicos , Fenótipo , Receptores de Antígenos de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Distribuição Tecidual , Transcriptoma
4.
J Exp Med ; 215(11): 2705-2714, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30232200

RESUMO

T follicular helper (Tfh) cells express transcription factor BCL-6 and cytokine IL-21. Mature Tfh cells are also capable of producing IFN-γ without expressing the Th1 transcription factor T-bet. Whether this IFN-γ-producing Tfh population represents a unique Tfh subset with a distinct differentiation pathway is poorly understood. By using T-bet fate-mapping mouse strains, we discovered that almost all the IFN-γ-producing Tfh cells have previously expressed T-bet and express high levels of NKG2D. DNase I hypersensitivity analysis indicated that the Ifng gene locus is partially accessible in this "ex-T-bet" population with a history of T-bet expression. Furthermore, multicolor tissue imaging revealed that the ex-T-bet Tfh cells found in germinal centers express IFN-γ in situ. Finally, we found that IFN-γ-expressing Tfh cells are absent in T-bet-deficient mice, but fully present in mice with T-bet deletion at late stages of T cell differentiation. Together, our findings demonstrate that transient expression of T-bet epigenetically imprints the Ifng locus for cytokine production in this Th1-like Tfh cell subset.


Assuntos
Diferenciação Celular/imunologia , Impressão Genômica/imunologia , Centro Germinativo/imunologia , Proteínas com Domínio T/imunologia , Células Th1/imunologia , Animais , Diferenciação Celular/genética , Centro Germinativo/citologia , Interferon gama/genética , Interferon gama/imunologia , Interleucinas/genética , Interleucinas/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/imunologia , Proteínas com Domínio T/genética , Células Th1/citologia
5.
Blood Adv ; 2(14): 1685-1690, 2018 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-30021780

RESUMO

Expression of the transcription factor T-cell factor 1 (TCF1) identifies antigen-experienced murine CD8+ T cells that retain potential for lymphoid recirculation and the ability to self-renew while producing more differentiated effector cells. We found that CD8+ T cells in the blood of both healthy and chronically infected humans expressed TCF1 at 3 distinct levels: high (TCF1-hi), intermediate (TCF1-int), and low (TCF1-lo). TCF1-hi cells could be found within both the naive and memory compartments and were characterized by relative quiescence and lack of immediate effector function. A substantial fraction of TCF1-int cells were found among memory cells, and TCF1-int cells exhibited robust immediate effector functions. TCF1-lo cells were most enriched in effector memory cells that expressed the senescence marker CD57. Following reactivation, TCF1-hi cells gave rise to TCF1-lo descendants while self-renewing the TCF1-hi progenitor. By contrast, reactivation of TCF1-lo cells produced more TCF1-lo cells without evidence of de-differentiating into TCF1-hi cells. Flow cytometric analyses of TCF1 expression from patient specimens may become a useful biomarker for adaptive immune function in response to vaccination, infection, autoimmunity, and cancer.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Regulação da Expressão Gênica , Fator 1-alfa Nuclear de Hepatócito/biossíntese , Memória Imunológica , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Fator 1-alfa Nuclear de Hepatócito/imunologia , Humanos , Masculino
6.
Immunohorizons ; 2(4): 119-128, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29707696

RESUMO

Regulatory T cells (Tregs) are crucial for suppressing autoimmunity and inflammation mediated by conventional T cells. To be useful, some Tregs should have overlapping specificity with relevant self-reactive or pathogen-specific clones. Whether matching recognition between Tregs and non-Tregs might arise through stochastic or deterministic mechanisms has not been addressed. We tested the hypothesis that some Tregs that arise in the thymus or that are induced during Ag-driven expansion of conventional CD4+ T cells might be clonally related to non-Tregs by virtue of asymmetric Foxp3 induction during cell division. We isolated mouse CD4+ thymocytes dividing in vivo, wherein sibling cells exhibited discordant expression of Foxp3 and CD25. Under in vitro conditions that stimulate induced Tregs from conventional mouse CD4+ T cells, we found a requirement for cell cycle progression to achieve Foxp3 induction. Moreover, a substantial fraction of sibling cell pairs arising from induced Treg stimulation also contained discordant expression of Foxp3. Division-linked yet asymmetric induction of Treg fate offers potential mechanisms to anticipate peripheral self-reactivity during thymic selection as well as produce precise, de novo counterregulation during CD4+ T cell-mediated immune responses.

7.
Immunol Cell Biol ; 96(8): 863-871, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29570858

RESUMO

Growth signals drive hematopoietic progenitor cells to proliferate and branch into divergent cell fates, but how unequal outcomes arise from a common progenitor is not fully understood. We used steady-state analysis of in vivo hematopoiesis and Fms-related tyrosine kinase 3 ligand (Flt3L)-induced in vitro differentiation of dendritic cells (DCs) to determine how growth signals regulate lineage bias. We found that Flt3L signaling induced anabolic activation and proliferation of DC progenitors, which was associated with DC differentiation. Perturbation of processes associated with quiescence and catabolism, including AMP-activated protein kinase signaling, fatty acid oxidation, or mitochondrial clearance increased development of cDC2 cells at the expense of cDC1 cells. Conversely, scavenging anabolism-associated reactive oxygen species skewed differentiation toward cDC1 cells. Sibling daughter cells of dividing DC progenitors exhibited unequal expression of the transcription factor interferon regulatory factor 8, which correlated with clonal divergence in FoxO3a signaling and population-level bifurcation of cell fate. We propose that unequal transmission of growth signals during cell division might support fate branches during proliferative expansion of progenitors.


Assuntos
Células Dendríticas/fisiologia , Ácidos Graxos/metabolismo , Células-Tronco Hematopoéticas/fisiologia , Fatores Reguladores de Interferon/metabolismo , Proteínas de Membrana/metabolismo , Animais , Diferenciação Celular , Linhagem da Célula , Proliferação de Células , Células Cultivadas , Citocinas/metabolismo , Hematopoese , Fatores Reguladores de Interferon/genética , Metabolismo dos Lipídeos , Metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
8.
Immunol Cell Biol ; 96(3): 241-242, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29427338

Assuntos
Linfócitos T
9.
Cell Rep ; 22(4): 860-868, 2018 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29420173

RESUMO

Unequal transmission of nutritive signaling during cell division establishes fate disparity between sibling lymphocytes, but how asymmetric signaling becomes organized is not understood. We show that receptor-associated class I phosphatidylinositol 3-kinase (PI3K) signaling activity, indexed by phosphatidylinositol (3,4,5)-trisphosphate (PIP3) staining, is spatially restricted to the microtubule-organizing center and subsequently to one pole of the mitotic spindle in activated T and B lymphocytes. Asymmetric PI3K activity co-localizes with polarization of antigen receptor components implicated in class I PI3K signaling and with facultative glucose transporters whose trafficking is PI3K dependent and whose abundance marks cells destined for differentiation. Perturbation of class I PI3K activity disrupts asymmetry of upstream antigen receptors and downstream glucose transporter traffic. The roles of PI3K signaling in nutrient utilization, proliferation, and gene expression may have converged with the conserved role of PI3K signaling in cellular symmetry breaking to form a logic for regenerative lymphocyte divisions.


Assuntos
Linfócitos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Diferenciação Celular , Humanos , Transdução de Sinais
10.
J Immunol ; 200(6): 1977-1981, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29440505

RESUMO

The T-box transcription factors T-bet and Eomesodermin (Eomes) instruct discrete stages in NK cell development. However, their role in the immune response of mature NK cells against pathogens remains unexplored. We used an inducible deletion system to elucidate the cell-intrinsic role of T-bet and Eomes in mature NK cells during the course of mouse CMV infection. We show both T-bet and Eomes to be necessary for the expansion of virus-specific NK cells, with T-bet upregulation induced by IL-12 signaling and STAT4 binding to a conserved enhancer region upstream of the Tbx21 loci. Interestingly, our data suggest maintenance of virus-specific memory NK cell numbers and phenotype was dependent on T-bet, but not Eomes. These findings uncover a nonredundant and stage-specific influence of T-box transcription factors in the antiviral NK cell response.


Assuntos
Memória Imunológica/imunologia , Células Matadoras Naturais/imunologia , Proteínas com Domínio T/imunologia , Animais , Infecções por Citomegalovirus/imunologia , Interleucina-12/imunologia , Camundongos , Fator de Transcrição STAT4/imunologia , Regulação para Cima/imunologia
11.
J Immunol ; 200(4): 1513-1526, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29305435

RESUMO

Agonists to the TNF/TNFR costimulatory receptors CD134 (OX40) and CD137 (4-1BB) elicit antitumor immunity. Dual costimulation with anti-CD134 plus anti-CD137 is particularly potent because it programs cytotoxic potential in CD8+ and CD4+ T cells. Cytotoxicity in dual-costimulated CD4 T cells depends on the T-box transcription factor eomesodermin (Eomes), which we report is induced via a mechanism that does not rely on IL-2, in contrast to CD8+ CTL, but rather depends on the CD8 T cell lineage commitment transcription factor Runx3, which supports Eomes expression in mature CD8+ CTLs. Further, Eomes and Runx3 were indispensable for dual-costimulated CD4 T cells to mediate antitumor activity in an aggressive melanoma model. Runx3 is also known to be expressed in standard CD4 Th1 cells where it fosters IFN-γ expression; however, the CD4 T cell lineage commitment factor ThPOK represses transcription of Eomes and other CD8 lineage genes, such as Cd8a Hence, CD4 T cells can differentiate into Eomes+ cytotoxic CD4+CD8+ double-positive T cells by terminating ThPOK expression. In contrast, dual-costimulated CD4 T cells express Eomes, despite the continued expression of ThPOK and the absence of CD8α, indicating that Eomes is selectively released from ThPOK repression. Finally, although Eomes was induced by CD137 agonist, but not CD134 agonist, administered individually, CD137 agonist failed to induce CD134-/- CD4 T cells to express Eomes or Runx3, indicating that both costimulatory pathways are required for cytotoxic Th1 programming, even when only CD137 is intentionally engaged with a therapeutic agonist.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Melanoma Experimental/imunologia , Proteínas com Domínio T/biossíntese , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/agonistas , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Animais , Diferenciação Celular/imunologia , Subunidade alfa 3 de Fator de Ligação ao Core/imunologia , Imunoterapia , Ativação Linfocitária/imunologia , Melanoma Experimental/metabolismo , Camundongos , Camundongos Transgênicos , Receptores OX40/agonistas , Receptores OX40/imunologia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo
13.
Immunohorizons ; 1(7): 156-161, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28944344

RESUMO

Anabolic metabolism in lymphocytes promotes plasmablast and cytotoxic T cell differentiation at the expense of self-renewal. Heightened expression and function of the transcription factor IFN regulatory factor 4 (IRF4) accompany enhanced anabolic induction and full commitment to functional differentiation in B cells and CD8+ T cells. In this study, we used a genetic approach to determine whether IRF4 plays an analogous role in Th1 cell induction. Our findings indicate that IRF4 promotes determined Th1 cell differentiation in tandem with anabolic metabolism of CD4+ T cells. IRF4-deficient CD4+ T cells stimulated in vitro exhibit impaired induction of Th1 gene expression and defective silencing of T cell factor 1 expression. IRF4-deficient CD4+ T cells also undergo a shift toward catabolic metabolism, with reduced mammalian target of rapamycin activation, cell size, and nutrient uptake, as well as increased mitochondrial clearance. These findings suggest that the ability to remodel metabolic states can be an essential gateway for altering cell fate.

14.
Trends Cell Biol ; 27(12): 946-954, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28818395

RESUMO

Activated lymphocytes perform a clonal balancing act, yielding a daughter cell that differentiates owing to intense PI3K signaling, alongside a self-renewing sibling cell with blunted anabolic signaling. Divergent cellular anabolism versus catabolism is emerging as a feature of several developmental and regenerative paradigms. Metabolism can dictate cell fate, in part, because lineage-specific regulators are embedded in the circuitry of conserved metabolic switches. Unequal transmission of PI3K signaling during regenerative divisions is reminiscent of compartmentalized PI3K activity during directed motility or polarized information flow in non-dividing cells. The diverse roles of PI3K pathways in membrane traffic, cell polarity, metabolism, and gene expression may have converged to instruct sibling cell feast and famine, thereby enabling clonal differentiation alongside self-renewal.


Assuntos
Diferenciação Celular/imunologia , Linhagem da Célula/imunologia , Polaridade Celular/imunologia , Linfócitos/imunologia , Animais , Divisão Celular/imunologia , Células Clonais , Humanos , Linfócitos/citologia , Linfócitos/metabolismo , Fosfatidilinositol 3-Quinases/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/imunologia
15.
JCI Insight ; 2(5): e90063, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28289707

RESUMO

Immaturity of the immune system of human fetuses and neonates is often invoked to explain their increased susceptibility to infection; however, the development of the fetal innate immune system in early life remains incompletely explored. We now show that the most mature NK cells found in adult (or postnatal) human circulation (CD94-CD16+) are absent during ontogeny. Human fetal NK cells were found to express the 2 signature T-box transcription factors essential for the development of all murine NK and NK-like cells, eomesodermin (Eomes) and T-bet. The single-cell pattern of Eomes and T-bet expression during ontogeny, however, revealed a stereotyped pattern of reciprocal dominance, with immature NK cells expressing higher amounts of Eomes and more mature NK cells marked by greater abundance of T-bet. We also observed a stereotyped pattern of tissue-specific NK cell maturation during human ontogeny, with fetal liver being more restrictive to NK cell maturity than fetal bone barrow, spleen, or lung. These results support the hypothesis that maturation of human NK cells has a discrete restriction until postnatal life, and provide a framework to better understand the increased susceptibility of fetuses and newborns to infection.


Assuntos
Células Matadoras Naturais/metabolismo , Proteínas com Domínio T/metabolismo , Adulto , Animais , Antígenos CD/imunologia , Diferenciação Celular , Suscetibilidade a Doenças/imunologia , Feto/metabolismo , Humanos , Lactente , Recém-Nascido , Células Matadoras Naturais/citologia , Camundongos
16.
J Exp Med ; 214(1): 39-47, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27923906

RESUMO

Upon infection, an activated CD4+ T cell produces terminally differentiated effector cells and renews itself for continued defense. In this study, we show that differentiation and self-renewal arise as opposing outcomes of sibling CD4+ T cells. After influenza challenge, antigen-specific cells underwent several divisions in draining lymph nodes (LN; DLNs) while maintaining expression of TCF1. After four or five divisions, some cells silenced, whereas some cells maintained TCF1 expression. TCF1-silenced cells were T helper 1-like effectors and concentrated in the lungs. Cells from earliest divisions were memory-like and concentrated in nondraining LN. TCF1-expressing cells from later divisions in the DLN could self-renew, clonally yielding a TCF1-silenced daughter cell as well as a sibling cell maintaining TCF1 expression. Some TCF1-expressing cells in DLNs acquired an alternative, follicular helper-like fate. Modeled differentiation experiments in vitro suggested that unequal PI3K/mechanistic target of rapamycin signaling drives intraclonal cell fate heterogeneity. Asymmetric division enables self-renewal to be coupled to production of differentiated CD4+ effector T cells during clonal selection.


Assuntos
Divisão Celular Assimétrica/fisiologia , Linfócitos T CD4-Positivos/imunologia , Animais , Divisão Celular , Células Cultivadas , Fator 1-alfa Nuclear de Hepatócito/análise , Fator 1-alfa Nuclear de Hepatócito/genética , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/fisiologia , Serina-Treonina Quinases TOR/fisiologia
17.
Cell Rep ; 17(12): 3142-3152, 2016 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-28009285

RESUMO

Regeneration requires related cells to diverge in fate. We show that activated lymphocytes yield sibling cells with unequal elimination of aged mitochondria. Disparate mitochondrial clearance impacts cell fate and reflects larger constellations of opposing metabolic states. Differentiation driven by an anabolic constellation of PI3K/mTOR activation, aerobic glycolysis, inhibited autophagy, mitochondrial stasis, and ROS production is balanced with self-renewal maintained by a catabolic constellation of AMPK activation, mitochondrial elimination, oxidative metabolism, and maintenance of FoxO1 activity. Perturbations up and down the metabolic pathways shift the balance of nutritive constellations and cell fate owing to self-reinforcement and reciprocal inhibition between anabolism and catabolism. Cell fate and metabolic state are linked by transcriptional regulators, such as IRF4 and FoxO1, with dual roles in lineage and metabolic choice. Instructing some cells to utilize nutrients for anabolism and differentiation while other cells catabolically self-digest and self-renew may enable growth and repair in metazoa.


Assuntos
Proteína Forkhead Box O1/genética , Fatores Reguladores de Interferon/genética , Ativação Linfocitária/genética , Linfócitos/metabolismo , Mitocôndrias/metabolismo , Animais , Autofagia/genética , Diferenciação Celular/genética , Proteína Forkhead Box O1/metabolismo , Glicólise , Hematopoese/genética , Fatores Reguladores de Interferon/metabolismo , Metabolismo/genética , Camundongos , Mitocôndrias/genética , Fosfatidilinositol 3-Quinases/genética , Espécies Reativas de Oxigênio/metabolismo , Regeneração/genética , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética
18.
Cell Rep ; 17(7): 1773-1782, 2016 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-27829149

RESUMO

Selected CD8+ T cells must divide, produce differentiated effector cells, and self-renew, often repeatedly. We now show that silencing expression of the transcription factor TCF1 marks loss of self-renewal by determined effector cells and that this requires cell division. In acute infections, the first three CD8+ T cell divisions produce daughter cells with unequal proliferative signaling but uniform maintenance of TCF1 expression. The more quiescent initial daughter cells resemble canonical central memory cells. The more proliferative, effector-prone cells from initial divisions can subsequently undergo division-dependent production of a TCF1-negative effector daughter cell along with a self-renewing TCF1-positive daughter cell, the latter also contributing to the memory cell pool upon resolution of infection. Self-renewal in the face of effector cell determination may promote clonal amplification and memory cell formation in acute infections, sustain effector regeneration during persistent subclinical infections, and be rate limiting, but remediable, in chronic active infections and cancer.


Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Autorrenovação Celular , Animais , Ciclo Celular , Diferenciação Celular , Divisão Celular , Proliferação de Células , Células Clonais , Inativação Gênica , Camundongos Endogâmicos C57BL , Fator 1 de Transcrição de Linfócitos T/metabolismo
19.
J Immunol ; 197(4): 1017-22, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27430722

RESUMO

The role of Ab and B cells in preventing infection is established. In contrast, the role of B cell responses in containing chronic infections remains poorly understood. IgG2a (IgG1 in humans) can prevent acute infections, and T-bet promotes IgG2a isotype switching. However, whether IgG2a and B cell-expressed T-bet influence the host-pathogen balance during persisting infections is unclear. We demonstrate that B cell-specific loss of T-bet prevents control of persisting viral infection. T-bet in B cells controlled IgG2a production, as well as mucosal localization, proliferation, glycosylation, and a broad transcriptional program. T-bet controlled a broad antiviral program in addition to IgG2a because T-bet in B cells was important, even in the presence of virus-specific IgG2a. Our data support a model in which T-bet is a universal controller of antiviral immunity across multiple immune lineages.


Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Coriomeningite Linfocítica/imunologia , Proteínas com Domínio T/imunologia , Animais , Separação Celular , Doença Crônica , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunoglobulina G/imunologia , Vírus da Coriomeningite Linfocítica , Camundongos , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos
20.
J Exp Med ; 213(3): 415-31, 2016 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-26903243

RESUMO

A common genetic alteration in acute myeloid leukemia is the internal tandem duplication (ITD) in FLT3, the receptor for cytokine FLT3 ligand (FLT3L). Constitutively active FLT3-ITD promotes the expansion of transformed progenitors, but also has pleiotropic effects on hematopoiesis. We analyzed the effect of FLT3-ITD on dendritic cells (DCs), which express FLT3 and can be expanded by FLT3L administration. Pre-leukemic mice with the Flt3(ITD) knock-in allele manifested an expansion of classical DCs (cDCs) and plasmacytoid DCs. The expansion originated in DC progenitors, was cell intrinsic, and was further enhanced in Flt3(ITD/ITD) mice. The mutation caused the down-regulation of Flt3 on the surface of DCs and reduced their responsiveness to Flt3L. Both canonical Batf3-dependent CD8(+) cDCs and noncanonical CD8(+) cDCs were expanded and showed specific alterations in their expression profiles. Flt3(ITD) mice showed enhanced capacity to support T cell proliferation, including a cell-extrinsic expansion of regulatory T (T reg) cells. Accordingly, these mice restricted alloreactive T cell responses during graft-versus-host reaction, but failed to control autoimmunity without T reg cells. Thus, the FLT3-ITD mutation directly affects DC development, indirectly modulating T cell homeostasis and supporting T reg cell expansion. We hypothesize that this effect of FLT3-ITD might subvert immunosurveillance and promote leukemogenesis in a cell-extrinsic manner.


Assuntos
Células Dendríticas/imunologia , Duplicação Gênica , Leucemia/genética , Leucemia/imunologia , Proteínas de Membrana/genética , Mutação/genética , Linfócitos T/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem da Célula , Proliferação de Células , Regulação para Baixo , Regulação Leucêmica da Expressão Gênica , Homeostase , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Transdução de Sinais
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