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1.
Science ; 376(6594): eabl5197, 2022 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-35549406

RESUMO

Despite their crucial role in health and disease, our knowledge of immune cells within human tissues remains limited. We surveyed the immune compartment of 16 tissues from 12 adult donors by single-cell RNA sequencing and VDJ sequencing generating a dataset of ~360,000 cells. To systematically resolve immune cell heterogeneity across tissues, we developed CellTypist, a machine learning tool for rapid and precise cell type annotation. Using this approach, combined with detailed curation, we determined the tissue distribution of finely phenotyped immune cell types, revealing hitherto unappreciated tissue-specific features and clonal architecture of T and B cells. Our multitissue approach lays the foundation for identifying highly resolved immune cell types by leveraging a common reference dataset, tissue-integrated expression analysis, and antigen receptor sequencing.


Assuntos
Linfócitos B , Aprendizado de Máquina , Análise de Sequência de RNA , Análise de Célula Única , Linfócitos T , Transcriptoma , Células Cultivadas , Humanos , Especificidade de Órgãos
2.
Am J Transplant ; 18(1): 74-88, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28719147

RESUMO

Organ donors are sources of physiologically healthy organs and tissues for life-saving transplantation, and have been recently used for human immunology studies which are typically confined to the sampling of peripheral blood. Donors comprise a diverse population with different causes of death and clinical outcomes during hospitalization, and the effects of such variations on immune parameters in blood and tissues are not known. We present here a coordinate analysis of innate and adaptive immune components in blood, lymphoid (bone marrow, spleen, lymph nodes), and mucosal (lungs, intestines) sites from a population of brain-dead organ donors (2 months-93 years; n = 291) across eight clinical parameters. Overall, the blood of donors exhibited similar monocyte and lymphocyte content and low serum levels of pro-inflammatory cytokines as healthy controls; however, donor blood had increased neutrophils and serum levels of IL-8, IL-6, and MCP-1 which varied with cause of death. In tissues, the frequency and composition of monocytes, neutrophils, B lymphocytes and T cell subsets in lymphoid or mucosal sites did not vary with clinical state, and was similar in donors independent of the extent of clinical complications. Our results reveal that organ donors maintain tissue homeostasis, and are a valuable resource for fundamental studies in human immunology.


Assuntos
Morte Encefálica/imunologia , Linfócitos/imunologia , Células Mieloides/imunologia , Transplante de Órgãos , Doadores de Tecidos , Obtenção de Tecidos e Órgãos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Morte Encefálica/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Citocinas/sangue , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Subpopulações de Linfócitos T/imunologia , Adulto Jovem
4.
Mucosal Immunol ; 8(6): 1313-23, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25850654

RESUMO

Group 2 innate lymphoid cells (ILC2s) promote type 2 cytokine-dependent immunity, inflammation, and tissue repair. Although epithelial cell-derived cytokines regulate ILC2 effector functions, the pathways that control the in vivo migration of ILC2s into inflamed tissues remain poorly understood. Here, we provide the first demonstration that expression of the prostaglandin D2 (PGD2) receptor CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) regulates the in vivo accumulation of ILC2s in the lung. Although a significant proportion of ILC2s isolated from healthy human peripheral blood expressed CRTH2, a smaller proportion of ILC2s isolated from nondiseased human lung expressed CRTH2, suggesting that dynamic regulation of CRTH2 expression might be associated with the migration of ILC2s into tissues. Consistent with this, murine ILC2s expressed CRTH2, migrated toward PGD2 in vitro, and accumulated in the lung in response to PGD2 in vivo. Furthermore, mice deficient in CRTH2 exhibited reduced ILC2 responses and inflammation in a murine model of helminth-induced pulmonary type 2 inflammation. Critically, adoptive transfer of CRTH2-sufficient ILC2s restored pulmonary inflammation in CRTH2-deficient mice. Together, these data identify a role for the PGD2-CRTH2 pathway in regulating the in vivo accumulation of ILC2s and the development of type 2 inflammation in the lung.


Assuntos
Imunidade Inata/imunologia , Linfócitos/imunologia , Pneumonia/imunologia , Prostaglandina D2/imunologia , Receptores Imunológicos/imunologia , Receptores de Prostaglandina/imunologia , Transferência Adotiva , Animais , Separação Celular , Quimiotaxia de Leucócito/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/metabolismo , Prostaglandina D2/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo
5.
Mucosal Immunol ; 7(3): 501-10, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24064670

RESUMO

The extent to which tissue-specific viral infections generate memory T cells specifically adapted to and maintained within the target infection site is unknown. Here, we show that respiratory virus-specific memory T cells in mice and humans are generated and maintained in compartmentalized niches in lungs, distinct from populations in lymphoid tissue or circulation. Using a polyclonal mouse model of influenza infection combined with an in vivo antibody labeling approach and confocal imaging, we identify a spatially distinct niche in the lung where influenza-specific T-cell responses are expanded and maintained long term as tissue-resident memory (T(RM)) CD4 and CD8 T cells. Lung T(RM) are further distinguished from circulating memory subsets in lung and spleen based on CD69 expression and persistence independent of lymphoid stores. In humans, influenza-specific T cells are enriched within the lung T(RM) subset, whereas memory CD8 T cells specific for the systemic virus cytomegalovirus are distributed in both lung and spleen, suggesting that the site of infection affects T(RM) generation. Our findings reveal a precise spatial organization to virus-specific T-cell memory, determined by the site of the initial infection, with important implications for the development of targeted strategies to boost immunity at appropriate tissue sites.


Assuntos
Memória Imunológica , Pulmão/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Modelos Animais de Doenças , Humanos , Imunofenotipagem , Vírus da Influenza A/imunologia , Pulmão/metabolismo , Pulmão/virologia , Ativação Linfocitária/imunologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Camundongos , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/metabolismo , Fenótipo , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
6.
Am J Transplant ; 12(5): 1124-32, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22299822

RESUMO

Donor pancreatic lymph node cells (PLNC) protect islet transplants in Non-obese diabetic (NOD) mice. We hypothesized that induced FoxP3(+) regulatory T cells (Tregs) were required for long-term islet engraftment. NOD or NOD.NON mice were treated with ALS (antilymphocyte serum) and transplanted with NOR islets +/-PLNC (5 × 10(7) ). In vivo proliferation and expansion of FoxP3(+) Tregs was monitored in spleen and PLN from ALS- and ALS/PLNC-treated recipient mice. Anti-CD25 depletion was used to determine the necessity of Tregs for tolerance. FoxP3(+) numbers significantly increased in ALS/PLNC-treated recipients compared to ALS-treated mice. In ALS/PLNC-treated mice, recipient-derived Tregs localized to the transplanted islets, and this was associated with intact, insulin-producing ß cells. Proliferation and expansion of FoxP3(+) Tregs was markedly increased in PLNC-treated mice with accepted islet grafts, but not in diabetic mice not receiving PLNC. Deletion of Tregs with anti-CD25 antibodies prevented islet graft tolerance and resulted in rejection. Adoptive transfer of Tregs to secondary NOD.scid recipients inhibited autoimmunity by cotransferred NOD effector T cells. Treg expansion induced by ALS/PLNC-treatment promoted long term islet graft survival. Strategies leading to Treg proliferation and localization to the transplant site represent a therapeutic approach to controlling recurrent autoimmunity.


Assuntos
Soro Antilinfocitário/administração & dosagem , Diabetes Mellitus Tipo 1/terapia , Sobrevivência de Enxerto/imunologia , Transplante das Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/imunologia , Linfonodos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade , Diabetes Mellitus Tipo 1/imunologia , Feminino , Imunofluorescência , Fatores de Transcrição Forkhead/metabolismo , Técnicas Imunoenzimáticas , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Tolerância ao Transplante/imunologia
7.
Proc Natl Acad Sci U S A ; 108(23): 9342-5, 2011 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-21597000

RESUMO

Many physical and chemical properties of the light rare-earths and actinides are governed by the active role of f electrons, and despite intensive efforts the details of the mechanisms of phase stability and transformation are not fully understood. A prominent example which has attracted a lot of interest, both experimentally and theoretically over the years is the isostructural γ - α transition in cerium. We have determined by inelastic X-ray scattering, the complete phonon dispersion scheme of elemental cerium across the γ → α transition, and compared it with theoretical results using ab initio lattice dynamics. Several phonon branches show strong changes in the dispersion shape, indicating large modifications in the interactions between phonons and conduction electrons. This is reflected as well by the lattice Grüneisen parameters, particularly around the X point. We derive a vibrational entropy change ΔS(γ-α)(vib) ≈ (0.33+/-0.03)k(B), illustrating the importance of the lattice contribution to the transition. Additionally, we compare first principles calculations with the experiments to shed light on the mechanism underlying the isostructural volume collapse in cerium under pressure.


Assuntos
Cério/química , Fenômenos Químicos , Modelos Químicos , Algoritmos , Cinética , Espalhamento a Baixo Ângulo , Difração de Raios X/métodos
8.
Phys Rev Lett ; 106(6): 065701, 2011 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-21405478

RESUMO

The cerium γ⇄α transition was investigated using high-pressure, high-temperature angle-dispersive x-ray diffraction measurements on both poly- and single-crystalline samples, explicitly addressing symmetry change and transformation paths. The isomorphic hypothesis of the transition is confirmed, with a transition line ending at a solid-solid critical point. The critical exponent is determined, showing a universal behavior that can be pictured as a liquid-gas transition. We further report an isomorphic transition between two single crystals (with more than 14% of volume difference), an unparalleled observation in solid-state matter interpreted in terms of dislocation-induced diffusionless first-order phase transformation.

9.
Mucosal Immunol ; 3(1): 29-39, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19865078

RESUMO

Toll-like receptors (TLRs) and proteinase-activated receptors (PARs) function as innate immune biosensors in mucosal epithelial cells (ECs). We previously reported the functional and physical interactions between TLR4 and PAR(2). We have extended these findings herein by showing the cooperation between PAR(2) and TLR2, TLR3, or TLR4 for activation of nuclear factor-kappaB-dependent signaling in mucosal EC lines. In contrast, activation of PAR(2) negatively regulated TLR3-dependent antiviral pathway, blunting the expression of TLR3/interferon regulatory factor-3 (IRF-3)-driven genes, as well as activation of IRF-3 and STAT1. Consistent with these in vitro observations, PAR(2)(-/-) and TLR4(-/-) mice, which were refractory to footpad edema induced by PAR(2) agonist peptide, were protected from mouse-adapted H1N1 influenza A virus-induced lethality when compared to wild-type (WT) mice. These data support and extend our recently described, novel model of PAR(2)-TLR4 "receptor cooperativity" and highlight the complexity of signaling integration between heterologous innate immune biosensors.


Assuntos
Células Epiteliais/metabolismo , Vírus da Influenza A Subtipo H1N1/imunologia , Infecções por Orthomyxoviridae/imunologia , Receptor PAR-2/metabolismo , Receptores Toll-Like/metabolismo , Animais , Linhagem Celular , Edema , Células Epiteliais/imunologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Humanos , Vírus da Influenza A Subtipo H1N1/patogenicidade , Fator Regulador 3 de Interferon/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membrana Mucosa/patologia , NF-kappa B/metabolismo , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/fisiopatologia , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/imunologia
10.
Am J Transplant ; 9(11): 2615-23, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19775313

RESUMO

T-cell depletion reportedly leads to alterations in the T-cell compartment with predominant survival of memory phenotype CD4 T cells. Here, we asked whether the prevalence of memory T cells postdepletion results from their inherent resistance to depletion and/or to the homeostatic expansion of naive T cells and their phenotypic conversion to memory, which is known to occur in lymphopenic conditions. Using a 'mosaic memory' mouse model with trackable populations of alloreactive memory T cells, we found that treatment with murine antithymocyte globulin (mATG) or antilymphocyte serum (ALS) effectively depleted alloreactive memory CD4 T cells, followed by rapid homeostatic proliferation of endogenous CD4 T cells peaking at 4 days postdepletion, with no homeostatic advantage to the antigen-specific memory population. Interestingly, naive (CD44lo) CD4 T cells exhibited the greatest increase in homeostatic proliferation following mATG treatment, divided more extensively compared to memory (CD44hi) CD4 T cells and converted to a memory phenotype. Our results provide novel evidence that memory CD4 T cells are susceptible to lymphodepletion and that the postdepletional T-cell compartment is repopulated to a significant extent by homeostatically expanded naive T cells in a mouse model, with important important implications for immune alterations triggered by induction therapy.


Assuntos
Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Memória Imunológica/imunologia , Procedimentos de Redução de Leucócitos , Imunologia de Transplantes , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Soro Antilinfocitário , Contagem de Linfócito CD4 , Divisão Celular/imunologia , Homeostase/imunologia , Imunofenotipagem , Isoantígenos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
11.
Am J Transplant ; 6(6): 1275-84, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16686752

RESUMO

Alloreactive memory T cells can significantly impact graft survival due to their enhanced functional capacities, diverse tissue distribution and resistance to tolerance induction and depletional strategies. However, their role in allograft rejection is not well understood primarily due to the lack of suitable in vivo models. In this study, we use a novel approach to generate long-lived polyclonal alloreactive memory CD4 T cells from adoptive transfer of alloantigen-activated precursors into mouse hosts. We demonstrate that CD25 upregulation is a marker for precursors to alloantigen-specific memory and have created a new mouse model that features an expanded population of polyclonal alloreactive memory T cells that is distinguishable from the naive T-cell population. Furthermore, we show that alloreactive memory T cells exhibit rapid recall effector responses with predominant IFN-gamma and IL-2 production, and mediate vigorous allograft rejection. Interestingly, while we found a heterogeneous distribution of allomemory T cells in lymphoid and nonlymphoid tissues, they were all predominantly of the effector-memory (CD62Llo) phenotype. Our results present a unique model for the generation and tracking of polyclonal allospecific memory CD4 T cells in vivo and reveal insights into the distinct and robust nature of alloreactive T-cell memory.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Rejeição de Enxerto/prevenção & controle , Memória Imunológica , Isoantígenos/imunologia , Transfusão de Linfócitos , Transplante Homólogo/imunologia , Transferência Adotiva , Animais , Citocinas/análise , Ativação Linfocitária , Transfusão de Linfócitos/métodos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Animais , Subpopulações de Linfócitos T/imunologia , Doadores de Tecidos , Imunologia de Transplantes
12.
Phys Rev Lett ; 93(21): 215505, 2004 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-15601029

RESUMO

The five independent elastic moduli of single-crystalline hcp cobalt were determined by inelastic x-ray scattering to 39 GPa and compared to ultrasonic measurements and first principles calculations. In general the agreement is good, in particular, for the evolution of the longitudinal sound velocity in the a-c plane. This confirms the calculations, suggesting that a similar evolution is valid for hcp iron, the main constituent of the Earth's inner core, up to the highest investigated pressure. Our results represent an important benchmark to further refine ab initio calculations.

13.
Scand J Immunol ; 58(2): 145-54, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12869135

RESUMO

Memory immune responses against foreign antigens protect the host from pathogens previously encountered via illness or vaccination, yet can also contribute to the pathology of autoimmune disease when generated against self-antigens. Memory immune responses are classically attributed to the reactivation of long-lived, antigen-specific T lymphocytes that arise directly from differentiated effector T cells and persist in a uniformly quiescent state. Recent findings in both humans and mice, using new biochemical, molecular and cellular approaches, have identified novel features of memory T cells providing new insight into models for memory cell development and differentiation. Biochemical and molecular studies on memory T cells have identified novel markers for memory T cells that may play integral roles in their generation and maintenance. Recent cellular immunological studies have uncovered remarkable heterogeneity amongst antigen-specific memory T cells. Memory cell heterogeneity in the expression of homing and chemokine receptor delineates functional subsets of memory T cells that differ in their proliferative capacity, differentiation potential, homing properties and protective abilities. These findings suggest that memory T cells with diverse properties residing in both lymphoid and nonlymphoid tissues may be necessary to elicit a rapid and effective protective recall immune response involving both cellular and humoral immunity.


Assuntos
Memória Imunológica/imunologia , Linfócitos T Reguladores/imunologia , Animais , Humanos , Ativação Linfocitária/imunologia , Camundongos , Receptores de Antígenos de Linfócitos T/imunologia
14.
Immunol Invest ; 30(2): 87-101, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11465674

RESUMO

The precise nature and development of the memory (CD45RO+) CD4+ T lymphocytes remain unknown. In this study, we analyzed differential gene expression of human memory CD4+ T lymphocytes in relation to their naive counterparts. A suppression subtractive hybridization technique was used to isolate and clone differentially expressed genes in the memory subset with respect to the naive subset. We screened approximately 300 clones by dot blot analysis and sequenced 23 differentially expressed clones. GenBank sequence homology search showed that these clones included genes for transcription factors, enzymes and immunomodulatory molecules. Differential expression of a subset of these genes was further confirmed by RT-PCR and densitometric analysis revealed that they were expressed five to eightfold more in memory than naive CD4+ T lymphocytes. Collectively, these results suggest that multiple genes with different functions contribute to the development of immunological memory in human T lymphocytes.


Assuntos
Linfócitos T CD4-Positivos , Expressão Gênica , Memória Imunológica , Antígenos Comuns de Leucócito , Linfócitos T CD4-Positivos/imunologia , Células Clonais , DNA Complementar , Humanos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
15.
Blood ; 97(12): 3851-9, 2001 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-11389026

RESUMO

Human effector T cells have been difficult to isolate and characterize due to their phenotypic and functional similarity to the memory subset. In this study, a biochemical approach was used to analyze human effector CD4 T cells generated in vitro by activation with anti-CD3 and autologous monocytes for 3 to 5 days. The resultant effector cells expressed the appropriate activation/differentiation markers and secreted high levels of interferon gamma (IFN-gamma) when restimulated. Biochemically, effector CD4 T cells exhibited increases in total intracellular tyrosine phosphorylation and effector-associated phosphorylated species. Paradoxically, these alterations in tyrosine phosphorylation were concomitant with greatly reduced expression of CD3zeta and CD3epsilon signaling subunits coincident with a reduction in surface T-cell receptor (TCR) expression. Because loss of CD3zeta has also been detected in T cells isolated ex vivo from individuals with cancer, chronic viral infection, and autoimmune diseases, the requirements and kinetics of CD3zeta down-regulation were examined. The loss of CD3zeta expression persisted throughout the course of effector T-cell differentiation, was reversible on removal from the activating stimulus, and was modulated by activation conditions. These biochemical changes occurred in effector T cells generated from naive or memory CD4 T-cell precursors and distinguished effector from memory T cells. The results suggest that human effector T-cell differentiation is accompanied by alterations in the TCR signal transduction and that loss of CD3zeta expression may be a feature of chronic T-cell activation and effector generation in vivo. (Blood. 2001;97:3851-3859)


Assuntos
Linfócitos T CD4-Positivos/imunologia , Complexo CD3/metabolismo , Linfócitos T CD4-Positivos/citologia , Técnicas de Cultura de Células , Diferenciação Celular/imunologia , Células Cultivadas , Regulação para Baixo , Humanos , Imunofenotipagem , Ativação Linfocitária/efeitos dos fármacos , Muromonab-CD3/farmacologia , Fosforilação , Receptores de Antígenos de Linfócitos T/metabolismo , Subpopulações de Linfócitos T , Tirosina/metabolismo
16.
J Immunol ; 166(2): 926-35, 2001 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-11145669

RESUMO

Defining the cellular composition of the memory T cell pool has been complicated by an inability to distinguish effector and memory T cells. We present here an activation profile assay, using anti-CD3 and antigenic stimuli, that clearly distinguishes effector and memory CD4 T cells and defines subsets of long-lived memory CD4 T cells based on CD62 ligand (CD62L) expression. The CD62L(low) memory subset functionally resembles effector cells, exhibiting hyper-responsiveness to antigenic and anti-CD3 mediated stimuli, high proliferative capacity, and rapid activation kinetics. The CD62L(high) memory subset functionally resembles resting memory cells, exhibiting hyporesponsiveness to anti-CD3 stimuli, lower proliferative capacity, and slower activation kinetics. Our results indicate that the memory CD4 T cell pool is heterogeneous, consisting of persisting effectors and resting memory T cells.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Memória Imunológica , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/transplante , Separação Celular , Sobrevivência Celular/imunologia , Citocinas/biossíntese , Epitopos de Linfócito T/imunologia , Citometria de Fluxo , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Antígenos de Histocompatibilidade Classe II , Interfase/imunologia , Selectina L/biossíntese , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/fisiologia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/transplante
17.
Clin Immunol ; 95(3): 173-81, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10866123

RESUMO

Immunological memory is manifested by the body's ability to enjoy long-term protection against specific pathogens previously encountered through illness or vaccination. This memory response resides in the long-lived, previously activated memory T and B lymphocytes that are believed to exist in a quiescent state. Recent advances in studies on T cell memory have revealed heterogeneity in the T cells that mediate memory responses that may have implications for the generation and maintenance of these cells over time. This review will present these recent findings on memory T cells in the context of past research and current models for the generation and persistence of memory T cells.


Assuntos
Memória Imunológica/fisiologia , Linfócitos T/imunologia , Animais , Heterogeneidade Genética , Humanos , Memória Imunológica/genética
18.
J Immunol ; 163(6): 3053-63, 1999 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-10477569

RESUMO

Memory T cell responses are believed to be mediated by long-lived memory T cells that arise directly from a subset of short-lived, activated effector T cells that have reverted to the resting state. Although widely accepted, definitive proof that memory T cells arise from effectors is lacking because of the inability to reliably distinguish these subsets based on known phenotypic or functional parameters. We have used a biochemical approach to distinguish effector and memory CD4 T cell subsets and follow the differentiative fate of effector cells in vivo. When examined biochemically, effector and memory CD4 T cells are strikingly distinct and exhibit qualitative and quantitative differences in tyrosine phosphorylation. These effector-specific patterns were identical in effectors derived either from naive CD4 T cells (primary effectors) or memory CD4 T cells (memory effectors). To monitor the fate of effector cells in vivo, Ag-activated CD4+ TCR-transgenic T cells were transferred into irradiated BALB/c mice. These TCR-transgenic CD4 T cells persisted in adoptive hosts for several months, gave a recall response to Ag, yet exhibited effector-specific biochemical profiles. These results suggest that a subset of effector CD4 T cells can persist in vivo and contribute to long-term immunity by mediating secondary immune responses.


Assuntos
Linfócitos T CD4-Positivos/química , Linfócitos T CD4-Positivos/citologia , Memória Imunológica , Subpopulações de Linfócitos T/química , Subpopulações de Linfócitos T/citologia , Transferência Adotiva , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/transplante , Diferenciação Celular/imunologia , Sobrevivência Celular/imunologia , Imunofenotipagem , Interfase/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Fosforilação , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/transplante
19.
J Immunol ; 161(11): 5855-61, 1998 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-9834064

RESUMO

Regulation of peripheral T cell responses is critical for preserving self tolerance. Memory T cells have a lower threshold for activation through the TCR and are thought to be less dependent on costimulation than naive T cells, suggesting a requirement for more stringent regulation of memory T cells. We have recently shown that CD4 engagement apart from the TCR results in the inactivation of memory, but not naive, CD4 T cells. We show here that this inhibition requires ligation of CTLA-4, in that blocking CTLA-4-B7 interactions restores memory CD4 T cell responsiveness. Early signaling through CTLA-4 is possible because resting memory, but not naive, CD4 T cells contain intracellular stores of CTLA-4 that are continuously recycled between the cytoplasm and the cell surface. This mechanism ensures that low intensity TCR engagements, which are thought to be important for peripheral T cell longevity, do not cause memory T cell activation but instead raise their threshold for costimulatory signals. This may give memory T cells an extended lifespan with a reduced risk of inappropriate activation.


Assuntos
Antígenos de Diferenciação/fisiologia , Linfócitos T CD4-Positivos/imunologia , Imunoconjugados , Memória Imunológica , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Abatacepte , Animais , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/farmacologia , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos CD , Antígenos de Diferenciação/biossíntese , Antígenos de Diferenciação/metabolismo , Antígeno B7-1/biossíntese , Antígeno B7-1/farmacologia , Sítios de Ligação de Anticorpos , Antígenos CD28/imunologia , Antígenos CD28/metabolismo , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/citologia , Antígeno CTLA-4 , Linhagem Celular , Membrana Celular/imunologia , Membrana Celular/metabolismo , Citoplasma/imunologia , Citoplasma/metabolismo , Feminino , Fibroblastos/imunologia , Fibroblastos/metabolismo , Antígenos de Histocompatibilidade Classe II/biossíntese , Antígenos de Histocompatibilidade Classe II/genética , Tolerância Imunológica/imunologia , Memória Imunológica/imunologia , Imunossupressores/farmacologia , Líquido Intracelular/imunologia , Líquido Intracelular/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Mutantes , Receptores Fc/metabolismo , Solubilidade , Subpopulações de Linfócitos T/citologia
20.
J Immunol ; 160(2): 535-9, 1998 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-9551883

RESUMO

There are currently two models for the generation of memory T cells: 1) memory T cells arise directly from activated effector T cells that have reverted to the resting state via an unknown mechanism; and 2) memory T cells are generated directly from naive T cells, bypassing an effector stage. I discuss here how recent results on the activation and signaling requirements of naive vs memory CD4 T cells favor the second model and how differential signaling of naive T cells may direct their developmental outcome.


Assuntos
Memória Imunológica , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/fisiologia , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Humanos
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