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1.
Immunity ; 39(5): 819-32, 2013 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-24238339

RESUMO

After antigen encounter by CD4(+) T cells, polarizing cytokines induce the expression of master regulators that control differentiation. Inactivation of the histone methyltransferase Ezh2 was found to specifically enhance T helper 1 (Th1) and Th2 cell differentiation and plasticity. Ezh2 directly bound and facilitated correct expression of Tbx21 and Gata3 in differentiating Th1 and Th2 cells, accompanied by substantial trimethylation at lysine 27 of histone 3 (H3K27me3). In addition, Ezh2 deficiency resulted in spontaneous generation of discrete IFN-γ and Th2 cytokine-producing populations in nonpolarizing cultures, and under these conditions IFN-γ expression was largely dependent on enhanced expression of the transcription factor Eomesodermin. In vivo, loss of Ezh2 caused increased pathology in a model of allergic asthma and resulted in progressive accumulation of memory phenotype Th2 cells. This study establishes a functional link between Ezh2 and transcriptional regulation of lineage-specifying genes in terminally differentiated CD4(+) T cells.


Assuntos
Regulação da Expressão Gênica , Histona-Lisina N-Metiltransferase/fisiologia , Complexo Repressor Polycomb 2/fisiologia , Subpopulações de Linfócitos T/citologia , Células Th1/citologia , Células Th2/citologia , Animais , Asma/genética , Asma/imunologia , Asma/patologia , Diferenciação Celular , Células Cultivadas/citologia , Células Cultivadas/imunologia , Células Cultivadas/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Fator de Transcrição GATA3/metabolismo , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/química , Histona-Lisina N-Metiltransferase/deficiência , Histona-Lisina N-Metiltransferase/genética , Histonas/metabolismo , Memória Imunológica , Testes de Liberação de Interferon-gama , Linfocinas/biossíntese , Linfocinas/genética , Masculino , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Complexo Repressor Polycomb 2/química , Complexo Repressor Polycomb 2/deficiência , Complexo Repressor Polycomb 2/genética , Processamento de Proteína Pós-Traducional , Deleção de Sequência , Proteínas com Domínio T/biossíntese , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Subpopulações de Linfócitos T/imunologia , Células Th1/imunologia , Células Th2/imunologia
2.
Proc Natl Acad Sci U S A ; 116(15): 7425-7430, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30910977

RESUMO

Serum IgG, which is mainly generated from IgG-secreting plasma cells in the bone marrow (BM), protects our body against various pathogens. We show here that the protein SiiE of Salmonella is both required and sufficient to prevent an efficient humoral immune memory against the pathogen by selectively reducing the number of IgG-secreting plasma cells in the BM. Attenuated SiiE-deficient Salmonella induces high and lasting titers of specific and protective Salmonella-specific IgG and qualifies as an efficient vaccine against Salmonella A SiiE-derived peptide with homology to laminin ß1 is sufficient to ablate IgG-secreting plasma cells from the BM, identifying laminin ß1 as a component of niches for IgG-secreting plasma cells in the BM, and furthermore, qualifies it as a unique therapeutic option to selectively ablate IgG-secreting plasma cells in autoimmune diseases and multiple myeloma.


Assuntos
Células da Medula Óssea/imunologia , Imunidade Humoral , Imunoglobulina G/imunologia , Memória Imunológica , Plasmócitos/imunologia , Salmonella/imunologia , Animais , Células da Medula Óssea/citologia , Imunoglobulina G/genética , Laminina/genética , Laminina/imunologia , Camundongos , Camundongos Knockout , Plasmócitos/citologia , Salmonella/genética
3.
Z Rheumatol ; 81(8): 660-666, 2022 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-35380249

RESUMO

Various research groups at the German Rheumatism Research Center in Berlin, in close cooperation with the Department of Rheumatology and Clinical Immunology of the Medical Clinic at the Charité, have made important contributions to the significance of B cells and plasma cells in rheumatic diseases, which are relevant not only for rheumatology but for all clinical specialties in which antibody-mediated diseases play a role. In particular, the research addresses impaired B cell homeostasis, the importance of the IgM Fc receptor in the regulation of autoimmunity, the role of long-lived memory plasma cells in maintaining autoimmunity and ensuring its survival in specific niches organized by stromal cells in bone marrow and inflamed tissues. The research results have contributed to a better understanding of the immunological and molecular mechanisms in rheumatic diseases and their treatment. The identification of the long-lived memory plasma cell has led to promising treatment approaches with curative potential in autoimmune diseases.


Assuntos
Doenças Autoimunes , Doenças Reumáticas , Autoimunidade , Linfócitos B , Humanos , Memória Imunológica , Plasmócitos , Doenças Reumáticas/terapia
4.
Immunol Rev ; 283(1): 86-98, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29664564

RESUMO

Memory for antigens once encountered is a hallmark of the immune system of vertebrates, providing us with an immunity adapted to pathogens of our environment. Despite its fundamental relevance, the cells and genes representing immunological memory are still poorly understood. Here we discuss the concept of a circulating, proliferating, and ubiquitous population of effector lymphocytes vs concepts of resting and dormant populations of dedicated memory lymphocytes, distinct from effector lymphocytes and residing in defined tissues, particularly in barrier tissues and in the bone marrow. The lifestyle of memory plasma cells of the bone marrow may serve as a paradigm, showing that persistence of memory lymphocytes is not defined by intrinsic "half-lives", but rather conditional on distinct survival signals provided by dedicated niches. These niches are organized by individual mesenchymal stromal cells. They define the capacity of immunological memory and regulate its homeostasis.


Assuntos
Células da Medula Óssea/imunologia , Medula Óssea/imunologia , Memória Imunológica , Animais , Medula Óssea/metabolismo , Células da Medula Óssea/metabolismo , Sobrevivência Celular/imunologia , Homeostase , Humanos , Ativação Linfocitária/imunologia , Especificidade de Órgãos/imunologia , Plasmócitos/imunologia , Plasmócitos/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
5.
Int Immunol ; 32(9): 589-595, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32766843

RESUMO

Long-term immunological memory mediated by CD4 T cells provides a rapid protection against previously encountered pathogens or antigens. However, it is still controversial how memory CD4 T cells are generated and maintained. Unclear definitions of T-cell memory may be partially responsible for this controversy. It is becoming clear that diverse pathways are responsible for the differentiation and long-term persistence of memory T cells. We herein discuss the diversity of memory cell generation, describing a novel population of resting memory CD4 T cells and their precursors.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Memória Imunológica/imunologia , Animais , Humanos
6.
Proc Natl Acad Sci U S A ; 115(6): 1334-1339, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29358404

RESUMO

The bone marrow maintains memory CD4 T cells, which provide memory to systemic antigens. Here we demonstrate that memory CD4 T cells are reactivated by antigen in the bone marrow. In a secondary immune response, antigen-specific T cells of the bone marrow mobilize and aggregate in immune clusters together with MHC class II-expressing cells, mostly B lymphocytes. They proliferate vigorously and express effector cytokines, but they do not develop into follicular T-helper cells. Neither do the B lymphocytes develop into germinal center B cells in the bone marrow. Within 10 days, the immune clusters disappear again. Within 30 days, the expanded antigen-specific memory CD4 T cells return to memory niches and are maintained again individually as resting cells. Thus, in secondary immune responses in the bone marrow T-cell memory is amplified, while in germinal center reactions of secondary lymphoid organs humoral memory is adapted by affinity maturation.


Assuntos
Medula Óssea/imunologia , Linfócitos T CD4-Positivos/imunologia , Memória Imunológica , Animais , Linfócitos B/imunologia , Medula Óssea/efeitos dos fármacos , Linfócitos T CD4-Positivos/citologia , Movimento Celular , Proliferação de Células , Cloridrato de Fingolimode/imunologia , Cloridrato de Fingolimode/farmacologia , Regulação da Expressão Gênica/imunologia , Imunização Secundária , Imunossupressores/farmacologia , Ativação Linfocitária , Masculino , Camundongos Endogâmicos C57BL , Receptores CXCR5/genética , Receptores CXCR5/imunologia , Baço/citologia , Baço/imunologia
7.
Immunol Rev ; 278(1): 87-100, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28658550

RESUMO

CD69 has been known as an early activation marker of lymphocytes; whereas, recent studies demonstrate that CD69 also has critical functions in immune responses. Early studies using human samples revealed the involvement of CD69 in various inflammatory diseases including asthma. Moreover, murine disease models using Cd69-/- mice and/or anti-CD69 antibody (Ab) treatment have revealed crucial roles for CD69 in inflammatory responses. However, it had not been clear how the CD69 molecule contributes to the pathogenesis of inflammatory diseases. We recently elucidated a novel mechanism, in which the interaction between CD69 and its ligands, myosin light chain 9, 12a and 12b (Myl9/12) play a critical role in the recruitment of activated T cells into the inflammatory lung. In this review, we first summarize CD69 function based on its structure and then introduce the evidence for the involvement of CD69 in human diseases and murine disease models. Then, we will describe how we discovered CD69 ligands, Myl9 and Myl12, and how the CD69-Myl9 system regulates airway inflammation. Finally, we will discuss possible therapeutic usages of the blocking Ab to the CD69-Myl9 system.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Hipersensibilidade/etiologia , Hipersensibilidade/metabolismo , Lectinas Tipo C/metabolismo , Cadeias Leves de Miosina/metabolismo , Animais , Antígenos CD/química , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T/química , Antígenos de Diferenciação de Linfócitos T/genética , Modelos Animais de Doenças , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Humanos , Hipersensibilidade/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , Lectinas Tipo C/química , Lectinas Tipo C/genética , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/etiologia , Hipersensibilidade Respiratória/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
8.
Immunity ; 35(5): 733-45, 2011 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-22118525

RESUMO

The regulation of memory CD4(+) helper T (Th) cell function, such as polarized cytokine production, remains unclear. Here we show that memory T helper 2 (Th2) cells are divided into four subpopulations by CD62L and CXCR3 expression. All four subpopulations produced interleukin-4 (IL-4) and IL-13, whereas only the CD62L(lo)CXCR3(lo) population produced IL-5 accompanied by increased H3-K4 methylation at the Il5 gene locus. The transcription factor Eomesodermin (encoded by Eomes) was highly expressed in memory Th2 cells, whereas its expression was selectively downregulated in the IL-5-producing cells. Il5 expression was enhanced in Eomes-deficient cells, and Eomesodermin was shown to interact with the transcription factor GATA3, preventing GATA3 binding to the Il5 promoter. Memory Th2 cell-dependent airway inflammation was attenuated in the absence of the CD62L(lo)CXCR3(lo) population but was enhanced by Eomes-deficient memory Th2 cells. Thus, IL-5 production in memory Th2 cells is regulated by Eomesodermin via the inhibition of GATA3 activity.


Assuntos
Fator de Transcrição GATA3/metabolismo , Memória Imunológica/imunologia , Interleucina-5/biossíntese , Proteínas com Domínio T/metabolismo , Células Th2/imunologia , Animais , Células Cultivadas , Fator de Transcrição GATA3/antagonistas & inibidores , Expressão Gênica , Inflamação/imunologia , Selectina L/metabolismo , Depleção Linfocítica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos Transgênicos , Regiões Promotoras Genéticas , Receptores CXCR3/metabolismo , Sistema Respiratório/imunologia , Proteínas com Domínio T/genética , Células Th2/metabolismo , Transcrição Gênica
9.
J Allergy Clin Immunol ; 144(2): 549-560.e10, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30851295

RESUMO

BACKGROUND: Natural killer T (NKT) cells express a T-cell receptor that recognizes endogenous and environmental glycolipid antigens. Several subsets of NKT cells have been identified, including IFN-γ-producing NKT1 cells, IL-4-producing NKT2 cells, and IL-17-producing NKT17 cells. However, little is known about the factors that regulate their differentiation and respective functions within the immune system. OBJECTIVE: We sought to determine whether the polycomb repressive complex 2 protein enhancer of zeste homolog 2 (Ezh2) restrains pathogenicity of NKT cells in the context of asthma-like lung disease. METHODS: Numbers of invariant natural killer T (iNKT) 1, iNKT2, and iNKT17 cells and tissue distribution, cytokine production, lymphoid tissue localization, and transcriptional profiles of iNKT cells from wild-type and Ezh2 knockout (KO) iNKT mice were determined. The contribution of NKT cells to development of spontaneous and house dust mite-induced airways pathology, including airways hyperreactivity (AHR) to methacholine, was also assessed in wild-type, Ezh2 KO, and Ezh2 KO mice lacking NKT cells. RESULTS: Ezh2 restrains development of pathogenic NKT cells, which induce spontaneous asthma-like disease in mice. Deletion of Ezh2 increased production of IL-4 and IL-13 and induced spontaneous AHR, lung inflammation, mucus production, and IgE. Increased IL-4 and IL-13 levels, AHR, lung inflammation, and IgE levels were all dependent on iNKT cells. In house dust mite-exposed animals Ezh2 KO resulted in enhanced AHR that was also dependent on iNKT cells. CONCLUSION: Ezh2 is a central regulator of iNKT pathogenicity and suppresses the ability of iNKT cells to induce asthma-like pathology.


Assuntos
Asma/imunologia , Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , Pulmão/imunologia , Células T Matadoras Naturais/imunologia , Animais , Asma/genética , Asma/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Pulmão/patologia , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/patologia , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/imunologia
10.
Eur J Immunol ; 47(11): 1900-1905, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28815584

RESUMO

It is current belief that numbers of CD8+ memory T lymphocytes in the memory phase of an immune response are maintained by homeostatic proliferation. Here, we compare the proliferation of CD8+ memory T lymphocytes, generated by natural infections and by intentional immunization, in spleen and bone marrow (BM). Fifty percent of CD8+ memory T lymphocytes in the spleen are eliminated by cyclophosphamide within 14 days, indicating that numbers of at least 50% of splenic CD8+ memory T lymphocytes are maintained by proliferation. The numbers of CD8+ memory T lymphocytes in the BM, however, were not affected by cyclophosphamide. This stability was independent of circulating CD8+ memory T cells, blocked by FTY720, showing that BM is a privileged site for the maintenance of memory T lymphocytes, as resident cells, resting in terms of proliferation.


Assuntos
Células da Medula Óssea/imunologia , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Baço/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Memória Imunológica/imunologia , Camundongos , Camundongos Endogâmicos C57BL
11.
Cytometry A ; 93(9): 876-888, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30107096

RESUMO

The bone marrow (BM) consists of multiple, structured micro-environmental entities-the so called niches, which contain hematopoietic cells as well as stromal cells. These niches fulfill a variety of functions, such as control of the hematopoietic stem cell pool, differentiation of hematopoietic cells, and maintenance of immunological memory. However, due to the molecular and cellular complexity and a lack of suitable histological multiplexing methods, the composition of the various BM niches is still elusive. In this study, we apply multiepitope-ligand-cartography (MELC) on bone sections from mice. We combine multiplexed immunofluorescence histology data with various object-based segmentation approaches in order to define irregularly shaped, net-like structures of stromal cells. We confirm MELC as a robust histological method and validate our automated segmentation algorithms using flow cytometry and manual evaluation. By means of MELC multiplexing, we reveal heterogeneous expression of leptin receptor (LpR), BP-1, and VCAM-1 in the stromal network. Moreover, we demonstrate by quantification a preferential contact of B cell subsets as well as of plasma cells to processes of CXCL12-expressing stromal cells, compared with stromal somata. In summary, our approach is suitable for spatial analysis of complex tissue structures.


Assuntos
Células da Medula Óssea/citologia , Medula Óssea/fisiologia , Células Estromais/citologia , Animais , Medula Óssea/metabolismo , Células da Medula Óssea/metabolismo , Células Cultivadas , Quimiocina CXCL12/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência/métodos , Receptores para Leptina/metabolismo , Células Estromais/metabolismo , Fatores de Transcrição/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
12.
Immunity ; 30(5): 721-30, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19427242

RESUMO

CD4(+) T lymphocytes are key to immunological memory. Here we show that in the memory phase of specific immune responses, most of the memory CD4(+) T lymphocytes had relocated into the bone marrow (BM) within 3-8 weeks after their generation-a process involving integrin alpha2. Antigen-specific memory CD4(+) T lymphocytes highly expressed Ly-6C, unlike most splenic CD44(hi)CD62L(-) CD4(+) T lymphocytes. In adult mice, more than 80% of Ly-6C(hi)CD44(hi)CD62L(-) memory CD4(+) T lymphocytes were in the BM. In the BM, they associated to IL-7-expressing VCAM-1(+) stroma cells. Gene expression and proliferation were downregulated, indicating a resting state. Upon challenge with antigen, they rapidly expressed cytokines and CD154 and efficiently induced the production of high-affinity antibodies by B lymphocytes. Thus, in the memory phase of immunity, memory helper T cells are maintained in BM as resting but highly reactive cells in survival niches defined by IL-7-expressing stroma cells.


Assuntos
Medula Óssea/imunologia , Linfócitos T CD4-Positivos/imunologia , Memória Imunológica , Animais , Antígenos Ly/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/metabolismo , Regulação para Baixo/imunologia , Expressão Gênica , Integrina alfa2/imunologia , Interleucina-7/imunologia , Interleucina-7/metabolismo , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Células Estromais/imunologia , Células Estromais/metabolismo
13.
Proc Natl Acad Sci U S A ; 111(25): 9229-34, 2014 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-24927527

RESUMO

In the bone marrow, a population of memory T cells has been described that promotes efficient secondary immune responses and has been considered to be preactivated, owing to its expression of CD69 and CD25. Here we show that human bone marrow professional memory T cells are not activated but are resting in terms of proliferation, transcription, and mobility. They are in the G0 phase of the cell cycle, and their transcriptome is that of resting T cells. The repertoire of CD4(+) bone marrow memory T cells compared with CD4(+) memory T cells from the blood is significantly enriched for T cells specific for cytomegalovirus-pp65 (immunodominant protein), tetanus toxoid, measles, mumps, and rubella. It is not enriched for vaccinia virus and Candida albicans-MP65 (immunodominant protein), typical pathogens of skin and/or mucosa. CD4(+) memory T cells specific for measles are maintained nearly exclusively in the bone marrow. Thus, CD4(+) memory T cells from the bone marrow provide long-term memory for systemic pathogens.


Assuntos
Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Células da Medula Óssea/imunologia , Linfócitos T CD4-Positivos/imunologia , Memória Imunológica/fisiologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Lectinas Tipo C/imunologia , Fase de Repouso do Ciclo Celular/imunologia , Adulto , Células da Medula Óssea/citologia , Linfócitos T CD4-Positivos/citologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Eur J Immunol ; 45(4): 975-87, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25639669

RESUMO

It is believed that memory CD8(+) T cells are maintained in secondary lymphoid tissues, peripheral tissues, and BM by homeostatic proliferation. Their survival has been shown to be dependent on IL-7, but it is unclear where they acquire it. Here we show that in murine BM, memory CD8(+) T cells individually colocalize with IL-7(+) reticular stromal cells. The T cells are resting in terms of global transcription and do not express markers of activation, for example, 4-1BB (CD137), IL-2, or IFN-γ, despite the expression of CD69 on about 30% of the cells. Ninety-five percent of the memory CD8(+) T cells in BM are in G0 phase of cell cycle and do not express Ki-67. Less than 1% is in S/M/G2 of cell cycle, according to propidium iodide staining. While previous publications have estimated the extent of proliferation of CD8(+) memory T cells on the basis of BrdU incorporation, we show here that BrdU itself induces proliferation of CD8(+) memory T cells. Taken together, the present results suggest that CD8(+) memory T cells are maintained as resting cells in the BM in dedicated niches with their survival conditional on IL-7 receptor signaling.


Assuntos
Células da Medula Óssea/citologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Fase de Repouso do Ciclo Celular/imunologia , Células Estromais/imunologia , Animais , Antígenos CD/biossíntese , Antígenos de Diferenciação de Linfócitos T/biossíntese , Células da Medula Óssea/imunologia , Proliferação de Células , Interferon gama/biossíntese , Interleucina-2/biossíntese , Interleucina-7/imunologia , Antígeno Ki-67/biossíntese , Lectinas Tipo C/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Transcrição Gênica , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/biossíntese
15.
Proc Natl Acad Sci U S A ; 109(19): 7409-14, 2012 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-22474373

RESUMO

Memory T-helper (Th) lymphocytes are crucial for the maintenance of acquired immunity to eliminate infectious pathogens. We have previously demonstrated that most memory Th lymphocytes reside and rest on stromal niches of the bone marrow (BM). Little is known, however, regarding the molecular basis for the generation and maintenance of BM memory Th lymphocytes. Here we show that CD69-deficient effector CD4 T lymphocytes fail to relocate into and persist in the BM and therefore to differentiate into memory cells. Consequently, CD69-deficient CD4 T cells fail to facilitate the production of high-affinity antibodies and the generation of BM long-lived plasma cells in the late phase of immune responses. Thus, CD69 is critical for the generation and maintenance of professional memory Th lymphocytes, which can efficiently help humoral immunity in the late phase. The deficit of immunological memory in CD69-deficient mice also highlights the essential role of BM for the establishment of Th memory.


Assuntos
Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Memória Imunológica/imunologia , Lectinas Tipo C/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Transferência Adotiva , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Medula Óssea/imunologia , Medula Óssea/metabolismo , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/transplante , Feminino , Citometria de Fluxo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , Microscopia Confocal , Células Estromais/imunologia , Células Estromais/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo
16.
Stem Cells ; 31(12): 2800-12, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23666739

RESUMO

The microenvironments, in which B lymphocytes develop in fetal liver, are largely still unknown. Among the nonhematopoietic cells, we have identified and FACS-separated two subpopulations, CD45(-) TER119(-) VCAM-1(+) cells that are either CD105(high) LYVE-1(high) or CD105(low) ALCAM(high) . Immunohistochemical analyses find three of four c-Kit(+) IL-7Rα(+) B220(low) CD19(-) SLC(-) B progenitors in contact with vascular endothelial-type LYVE-1(high) cells on embryonic day 13.5. One day later c-Kit(+) IL-7Rα(+) cells develop to CD19(- and +) , SLC-expressing, DHJH-rearranged pre/pro and pro/preB-I cells. Less than 10% are still in contact with LYVE-1(high) cells, but half of them are now in contact with mesenchymally derived ALCAM(high) liver cells. All of these ALCAM(high) cells, but not the LYVE-1(high) cells produce IL-7 and CXCL12, while both produce CXCL10. Progenitors and pro/preB-I cells are chemoattracted in vitro toward CXCL10 and 12, suggesting that lymphoid progenitors with Ig gene loci in germline configuration enter the developing fetal liver at E13.5 from vascular endothelium, attracted by CXCL10, and then migrate within a day to an ALCAM(high) liver cell microenvironment, differentiating to DHJH-rearranging, surrogate light chain-expressing pre/proB and pro/preB-I cells, attracted by CXCL10 and 12. Between E15.5 and E16.5 preB-I cells expand 10-fold in continued contact with ALCAM(high) cells and begin VH- to DHJH-rearrangements in further differentiated c-Kit(-) IL-7Rα(-) preBII cells. STEM Cells 2013;31:2800-2812.


Assuntos
Linfócitos B/citologia , Fígado/citologia , Fígado/embriologia , Células Precursoras de Linfócitos B/citologia , Animais , Linfócitos B/metabolismo , Diferenciação Celular/fisiologia , Movimento Celular/fisiologia , Microambiente Celular/fisiologia , Feminino , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
17.
Immunol Cell Biol ; 91(8): 524-31, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23897120

RESUMO

CD4 T cells play a key role in immunological memory. We have demonstrated that professional memory CD4 T cells reside and rest in the bone marrow (BM). However, the molecular mechanisms of their establishment in the BM and their maintenance remain unclear. We here show that memory CD4 T cells express high levels of CD49b and that CD49b-deficient or -blocked memory CD4 T-cell precursors fail to migrate from blood into the marrow of the bone, and they especially fail to transmigrate through sinusoidal endothelial cells of the BM. In the marrow, memory CD4 T cells and the precursors contact stromal cells expressing collagen II that are specific ligands for CD49b. Interestingly, memory CD4 T cells on day 117 of an immune response also dock on IL-7(+)/collagen XI(+) stromal cells, whereas memory precursors on day 12 do not. These results indicate that the collagen receptor CD49b is required for the migration of memory CD4 T-cell precursors into their survival niches of the bone marrow.


Assuntos
Medula Óssea/metabolismo , Integrina alfa2/metabolismo , Células Precursoras de Linfócitos T/imunologia , Células Estromais/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Medula Óssea/patologia , Antígenos CD4/metabolismo , Comunicação Celular , Diferenciação Celular/genética , Movimento Celular/genética , Células Cultivadas , Colágeno Tipo II/metabolismo , Colágeno Tipo XI/metabolismo , Memória Imunológica/genética , Integrina alfa2/genética , Interleucina-7/genética , Interleucina-7/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Migração Transendotelial e Transepitelial/genética
18.
Int Arch Allergy Immunol ; 161 Suppl 2: 118-24, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23711862

RESUMO

BACKGROUND: Recent studies have shown that prolonged Th2-type immune inflammation in the lung induces pulmonary arterial remodeling, in part through the induction of resistin-like molecule α (RELMα) expression. However, the role of interleukin-25 (IL-25; which promotes this inflammation) in the development of the pulmonary arterial remodeling remains unknown. METHODS: Ovalbumin (OVA)-sensitized C57BL/6 mice were challenged with OVA inhalation 3 times a week for 3 weeks. The effects of neutralizing anti-IL-25 antibody on OVA-induced pulmonary arterial remodeling and RELMα expression in the lung were examined. The pulmonary arterial remodeling and RELMα expression in the lung were examined in lung-specific IL-25 transgenic mice (CC10 IL-25 mice) and CC10 IL-25 mice in a natural killer T (NKT) cell-deficient background (CC10 IL-25 NKT(-/-) mice). RESULTS: Repeated OVA inhalation induced pulmonary arterial wall thickening and the expression of IL-25 and RELMα mRNA in the lung in OVA-sensitized mice. Injection of neutralizing anti-IL-25 antibody inhibited OVA-induced pulmonary arterial wall thickening and RELMα expression in the lung. CC10 IL-25 mice, but not CC10 IL-25 NKT(-/-) mice, spontaneously developed pulmonary arterial wall thickening and RELMα expression in the lung at 6 months of age. CONCLUSIONS: Prolonged expression of IL-25 in the lung induces pulmonary arterial wall thickening by NKT cell-dependent mechanisms.


Assuntos
Interleucina-17/imunologia , Células T Matadoras Naturais/imunologia , Artéria Pulmonar/imunologia , Artéria Pulmonar/patologia , Animais , Antígenos/imunologia , Feminino , Interleucina-17/genética , Camundongos , Camundongos Transgênicos , Células T Matadoras Naturais/metabolismo , Ovalbumina/imunologia , Artéria Pulmonar/metabolismo , Uteroglobina/genética , Uteroglobina/imunologia
19.
Cell Mol Life Sci ; 69(10): 1609-13, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22460581

RESUMO

Established views on the maintenance of immunological memory have been challenged recently by the description of memory plasma cells and memory T helper (Th) lymphocytes residing in the bone marrow (BM) in dedicated survival niches, resting in terms of proliferation and migration. While memory plasma cells are no longer reactive to antigen, memory Th lymphocytes are in a state of attentive rest, and can be reactivated fast and efficiently. Here, we discuss the signals controlling these resting states, which the memory lymphocytes receive from their microenvironment.


Assuntos
Células da Medula Óssea/imunologia , Medula Óssea/imunologia , Memória Imunológica , Ativação Linfocitária , Linfócitos T Auxiliares-Indutores/imunologia , Células da Medula Óssea/metabolismo , Microambiente Celular , Epigênese Genética , Linfócitos T Auxiliares-Indutores/metabolismo
20.
J Immunol ; 184(8): 4510-20, 2010 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-20237291

RESUMO

Polycomb group (PcG) gene products regulate the maintenance of homeobox gene expression in Drosophila and vertebrates. In the immune system, PcG molecules control cell cycle progression of thymocytes, Th2 cell differentiation, and the generation of memory CD4 T cells. In this paper, we extended the study of PcG molecules to the regulation of in vivo Th2 responses, especially allergic airway inflammation, by using conditional Ring1B-deficient mice with a CD4 T cell-specific deletion of the Ring1B gene (Ring1B(-/-) mice). In Ring1B(-/-) mice, CD4 T cell development appeared to be normal, whereas the differentiation of Th2 cells but not Th1 cells was moderately impaired. In an Ag-induced Th2-driven allergic airway inflammation model, eosinophilic inflammation was attenuated in Ring1B(-/-) mice. Interestingly, Ring1B(-/-) effector Th2 cells were highly susceptible to apoptosis in comparison with wild-type effector Th2 cells in vivo and in vitro. The in vitro experiments revealed that the expression of Bim was increased at both the transcriptional and protein levels in Ring1B(-/-) effector Th2 cells, and the enhanced apoptosis in Ring1B(-/-) Th2 cells was rescued by the knockdown of Bim but not the other proapoptotic genes, such as Perp, Noxa, or Bax. The enhanced apoptosis detected in the transferred Ring1B(-/-) Th2 cells in the lung of the recipient mice was also rescued by knockdown of Bim. Therefore, these results indicate that Ring1B plays an important role in Th2-driven allergic airway inflammation through the control of Bim-dependent apoptosis of effector Th2 cells in vivo.


Assuntos
Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Apoptose/imunologia , Mediadores da Inflamação/fisiologia , Pulmão/imunologia , Pulmão/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Repressoras/fisiologia , Células Th2/imunologia , Animais , Apoptose/genética , Proteínas Reguladoras de Apoptose/deficiência , Proteínas Reguladoras de Apoptose/fisiologia , Proteína 11 Semelhante a Bcl-2 , Células Cultivadas , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Imunofenotipagem , Pulmão/metabolismo , Proteínas de Membrana/deficiência , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Complexo Repressor Polycomb 1 , Proteínas do Grupo Polycomb , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/fisiologia , Células Th2/metabolismo , Células Th2/patologia
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