Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
Add more filters










Database
Language
Publication year range
1.
Cell ; 159(4): 814-28, 2014 Nov 06.
Article in English | MEDLINE | ID: mdl-25417158

ABSTRACT

Mechanisms for human memory T cell differentiation and maintenance have largely been inferred from studies of peripheral blood, though the majority of T cells are found in lymphoid and mucosal sites. We present here a multidimensional, quantitative analysis of human T cell compartmentalization and maintenance over six decades of life in blood, lymphoid, and mucosal tissues obtained from 56 individual organ donors. Our results reveal that the distribution and tissue residence of naive, central, and effector memory, and terminal effector subsets is contingent on both their differentiation state and tissue localization. Moreover, T cell homeostasis driven by cytokine or TCR-mediated signals is different in CD4+ or CD8+ T cell lineages, varies with their differentiation stage and tissue localization, and cannot be inferred from blood. Our data provide an unprecedented spatial and temporal map of human T cell compartmentalization and maintenance, supporting distinct pathways for human T cell fate determination and homeostasis.


Subject(s)
Aging/immunology , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Adolescent , Adult , Aged , CD28 Antigens/metabolism , Cell Differentiation , Child , Child, Preschool , Humans , Interleukin-7 Receptor alpha Subunit/metabolism , Lymphoid Tissue/cytology , Lymphoid Tissue/immunology , Middle Aged , Mucous Membrane/cytology , Mucous Membrane/immunology , Receptors, Antigen, T-Cell/chemistry , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes/metabolism , Tissue Donors , Young Adult
2.
Immunity ; 38(1): 187-97, 2013 Jan 24.
Article in English | MEDLINE | ID: mdl-23260195

ABSTRACT

Knowledge of human T cells derives chiefly from studies of peripheral blood, whereas their distribution and function in tissues remains largely unknown. Here, we present a unique analysis of human T cells in lymphoid and mucosal tissues obtained from individual organ donors, revealing tissue-intrinsic compartmentalization of naive, effector, and memory subsets conserved between diverse individuals. Effector memory CD4(+) T cells producing IL-2 predominated in mucosal tissues and accumulated as central memory subsets in lymphoid tissue, whereas CD8(+) T cells were maintained as naive subsets in lymphoid tissues and IFN-γ-producing effector memory CD8(+) T cells in mucosal sites. The T cell activation marker CD69 was constitutively expressed by memory T cells in all tissues, distinguishing them from circulating subsets, with mucosal memory T cells exhibiting additional distinct phenotypic and functional properties. Our results provide an assessment of human T cell compartmentalization as a new baseline for understanding human adaptive immunity.


Subject(s)
Immunologic Memory/immunology , T-Lymphocyte Subsets/immunology , Adolescent , Adult , Age Factors , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Female , Humans , Immunophenotyping , Integrin alpha Chains/metabolism , Lectins, C-Type/metabolism , Male , Middle Aged , Mucous Membrane/immunology , Organ Specificity/immunology , T-Lymphocyte Subsets/metabolism , Tissue Donors , Young Adult
3.
Science ; 336(6086): 1321-5, 2012 Jun 08.
Article in English | MEDLINE | ID: mdl-22674331

ABSTRACT

The mammalian intestinal tract is colonized by trillions of beneficial commensal bacteria that are anatomically restricted to specific niches. However, the mechanisms that regulate anatomical containment remain unclear. Here, we show that interleukin-22 (IL-22)-producing innate lymphoid cells (ILCs) are present in intestinal tissues of healthy mammals. Depletion of ILCs resulted in peripheral dissemination of commensal bacteria and systemic inflammation, which was prevented by administration of IL-22. Disseminating bacteria were identified as Alcaligenes species originating from host lymphoid tissues. Alcaligenes was sufficient to promote systemic inflammation after ILC depletion in mice, and Alcaligenes-specific systemic immune responses were associated with Crohn's disease and progressive hepatitis C virus infection in patients. Collectively, these data indicate that ILCs regulate selective containment of lymphoid-resident bacteria to prevent systemic inflammation associated with chronic diseases.


Subject(s)
Alcaligenes/physiology , Interleukins/immunology , Intestines/immunology , Lymphocytes/immunology , Lymphoid Tissue/immunology , Lymphoid Tissue/microbiology , Adult , Alcaligenes/immunology , Alcaligenes/isolation & purification , Animals , Bacterial Translocation , Crohn Disease/immunology , Crohn Disease/microbiology , Hepatitis C, Chronic/immunology , Hepatitis C, Chronic/microbiology , Humans , Immunity, Innate , Inflammation , Interleukins/administration & dosage , Interleukins/biosynthesis , Intestines/microbiology , Leukocyte L1 Antigen Complex/metabolism , Liver/microbiology , Lymph Nodes/immunology , Macaca mulatta , Mice , Mice, Inbred C57BL , Middle Aged , Spleen/microbiology , Young Adult , Interleukin-22
4.
Nat Immunol ; 12(11): 1045-54, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21946417

ABSTRACT

Innate lymphoid cells (ILCs), a heterogeneous cell population, are critical in orchestrating immunity and inflammation in the intestine, but whether ILCs influence immune responses or tissue homeostasis at other mucosal sites remains poorly characterized. Here we identify a population of lung-resident ILCs in mice and humans that expressed the alloantigen Thy-1 (CD90), interleukin 2 (IL-2) receptor a-chain (CD25), IL-7 receptor a-chain (CD127) and the IL-33 receptor subunit T1-ST2. Notably, mouse ILCs accumulated in the lung after infection with influenza virus, and depletion of ILCs resulted in loss of airway epithelial integrity, diminished lung function and impaired airway remodeling. These defects were restored by administration of the lung ILC product amphiregulin. Collectively, our results demonstrate a critical role for lung ILCs in restoring airway epithelial integrity and tissue homeostasis after infection with influenza virus.


Subject(s)
Homeostasis , Immunity, Innate , Influenza, Human/immunology , Lung/metabolism , Orthomyxoviridae Infections/immunology , Orthomyxoviridae/immunology , Respiratory Mucosa/metabolism , Airway Remodeling/drug effects , Airway Remodeling/immunology , Amphiregulin , Animals , Antigens, CD/biosynthesis , Cells, Cultured , EGF Family of Proteins , Glycoproteins/pharmacology , Homeostasis/immunology , Humans , Intercellular Signaling Peptides and Proteins/pharmacology , Interleukin-33 , Interleukins/metabolism , Lung/immunology , Lung/pathology , Lung/virology , Mice , Mice, Inbred C57BL , Respiratory Mucosa/immunology , Respiratory Mucosa/pathology , Respiratory Mucosa/virology , Wound Healing
5.
Immunity ; 33(4): 597-606, 2010 Oct 29.
Article in English | MEDLINE | ID: mdl-20933441

ABSTRACT

Dendritic cells (DCs) comprise distinct functional subsets including CD8⁻ and CD8(+) classical DCs (cDCs) and interferon-secreting plasmacytoid DCs (pDCs). The cytokine Flt3 ligand (Flt3L) controls the development of DCs and is particularly important for the pDC and CD8(+) cDC and their CD103(+) tissue counterparts. We report that mammalian target of rapamycin (mTOR) inhibitor rapamycin impaired Flt3L-driven DC development in vitro, with the pDCs and CD8(+)-like cDCs most profoundly affected. Conversely, deletion of the phosphoinositide 3-kinase (PI3K)-mTOR negative regulator Pten facilitated Flt3L-driven DC development in culture. DC-specific Pten targeting in vivo caused the expansion of CD8(+) and CD103(+) cDC numbers, which was reversible by rapamycin. The increased CD8(+) cDC numbers caused by Pten deletion correlated with increased susceptibility to the intracellular pathogen Listeria. Thus, PI3K-mTOR signaling downstream of Flt3L controls DC development, and its restriction by Pten ensures optimal DC pool size and subset composition.


Subject(s)
Dendritic Cells/physiology , Intracellular Signaling Peptides and Proteins/physiology , Membrane Proteins/physiology , Protein Serine-Threonine Kinases/physiology , Signal Transduction/physiology , Animals , Antigens, CD/analysis , CD8-Positive T-Lymphocytes/immunology , Cells, Cultured , Integrin alpha Chains/analysis , Listeriosis/immunology , Mice , Mice, Inbred C57BL , PTEN Phosphohydrolase/physiology , Phosphatidylinositol 3-Kinases/physiology , Sirolimus/pharmacology , TOR Serine-Threonine Kinases
6.
Mol Microbiol ; 77(2): 444-55, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20497329

ABSTRACT

Bacteriophage T4 is decorated with 155 copies of the highly antigenic outer capsid protein, Hoc. The Hoc molecule (40 kDa) is present at the centre of each hexameric capsomer and provides a good platform for surface display of pathogen antigens. Biochemical and modelling studies show that Hoc consists of a string of four domains, three immunoglobulin (Ig)-like and one non-Ig domain at the C-terminus. Biochemical data suggest that the Hoc protein has two functional modules, a capsid binding module containing domains 1 and 4 and a solvent-exposed module containing domains 2 and 3. This model is consistent with the dumbbell-shaped cryo-EM density of Hoc observed in the reconstruction of the T4 capsid. Mutagenesis localized the capsid binding site to the C-terminal 25 amino acids, which are predicted to form two beta-strands flanking a capsid binding loop. Mutations in the loop residues, ESRNG, abolished capsid binding, suggesting that these residues might interact with the major capsid protein, gp23*. With the conserved capsid binding module forming a foothold on the virus and the solvent-exposed module able to adapt to bind to a variety of surfaces, Hoc probably provides survival advantages to the phage, such as increasing the virus concentration near the host, efficient dispersion of the virus and exposing the tail for more efficient contact with the host cell surface prior to infection.


Subject(s)
Bacteriophage T4/chemistry , Capsid Proteins/chemistry , Amino Acid Sequence , Bacteriophage T4/immunology , Binding Sites , Capsid Proteins/immunology , Models, Molecular , Molecular Sequence Data , Mutation , Protein Interaction Domains and Motifs , Protein Structure, Tertiary , Sequence Alignment
7.
J Virol ; 80(15): 7688-98, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16840347

ABSTRACT

Bacteriophage T4 capsid is an elongated icosahedron decorated with 155 copies of Hoc, a nonessential highly antigenic outer capsid protein. One Hoc monomer is present in the center of each major capsid protein (gp23*) hexon. We describe an in vitro assembly system which allows display of HIV antigens, p24-gag, Nef, and an engineered gp41 C-peptide trimer, on phage T4 capsid surface through Hoc-capsid interactions. In-frame fusions were constructed by splicing the human immunodeficiency virus (HIV) genes to the 5' or 3' end of the Hoc gene. The Hoc fusion proteins were expressed, purified, and displayed on hoc(-) phage particles in a defined in vitro system. Single or multiple antigens were efficiently displayed, leading to saturation of all available capsid binding sites. The displayed p24 was highly immunogenic in mice in the absence of any external adjuvant, eliciting strong p24-specific antibodies, as well as Th1 and Th2 cellular responses with a bias toward the Th2 response. The phage T4 system offers new direction and insights for HIV vaccine development with the potential to increase the breadth of both cellular and humoral immune responses.


Subject(s)
AIDS Vaccines , Bacteriophage T4/metabolism , Capsid Proteins/metabolism , Capsid/metabolism , HIV Antigens/immunology , HIV Core Protein p24/immunology , HIV-1/immunology , Recombinant Fusion Proteins/metabolism , Animals , Bacteriophage T4/genetics , Bacteriophage T4/immunology , Capsid/immunology , Capsid Proteins/genetics , Female , HIV Antigens/genetics , HIV Antigens/metabolism , HIV-1/genetics , Humans , Mice , Mice, Inbred BALB C , Peptide Fragments/immunology , Protein Binding , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunology , Vaccines, Synthetic/immunology
8.
Virology ; 345(1): 190-8, 2006 Feb 05.
Article in English | MEDLINE | ID: mdl-16316672

ABSTRACT

An in vitro binding system is described to display large full-length proteins on bacteriophage T4 capsid surface at high density. The phage T4 icosahedral capsid features 155 copies of a nonessential highly antigenic outer capsid protein, Hoc, at the center of each major capsid protein hexon. Gene fusions were engineered to express the 83-kDa protective antigen (PA) from Bacillus anthracis fused to the N-terminus of Hoc and the 130-kDa PA-Hoc protein was expressed in Escherichia coli and purified. The purified PA-Hoc was assembled in vitro on hoc(-) phage particles. Binding was specific, stable, and of high affinity. This defined in vitro system allowed manipulation of the copy number of displayed PA and imposed no significant limitation on the size of the displayed antigen. In contrast to in vivo display systems, the in vitro approach allows all the capsid binding sites to be occupied by the 130-kDa PA-Hoc fusion protein. The PA-T4 particles were immunogenic in mice in the absence of an adjuvant, eliciting strong PA-specific antibodies and anthrax lethal toxin neutralizing antibodies. The in vitro display on phage T4 offers a novel platform for potential construction of customized vaccines against anthrax and other infectious diseases.


Subject(s)
Antigens, Bacterial/metabolism , Bacterial Toxins/metabolism , Bacteriophage T4/metabolism , Capsid Proteins/metabolism , Capsid/metabolism , Peptide Library , Recombinant Fusion Proteins/metabolism , Animals , Antibodies, Bacterial/blood , Antigens, Bacterial/genetics , Antigens, Bacterial/immunology , Antigens, Bacterial/isolation & purification , Artificial Gene Fusion , Bacterial Toxins/genetics , Bacterial Toxins/immunology , Bacterial Toxins/isolation & purification , Bacteriophage T4/genetics , Bacteriophage T4/immunology , Capsid/immunology , Capsid Proteins/genetics , Electrophoresis, Polyacrylamide Gel , Enzyme-Linked Immunosorbent Assay , Escherichia coli/genetics , Escherichia coli/metabolism , Mice , Mice, Inbred CBA , Protein Binding , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunology , Recombinant Fusion Proteins/isolation & purification
SELECTION OF CITATIONS
SEARCH DETAIL
...