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1.
Nat Immunol ; 16(4): 406-14, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25706747

ABSTRACT

We report that oral infection with Yersinia pseudotuberculosis results in the development of two distinct populations of pathogen-specific CD8(+) tissue-resident memory T cells (TRM cells) in the lamina propria. CD103(-) T cells did not require transforming growth factor-ß (TGF-ß) signaling but were true resident memory cells. Unlike CD103(+)CD8(+) T cells, which were TGF-ß dependent and were scattered in the tissue, CD103(-)CD8(+) T cells clustered with CD4(+) T cells and CX3CR1(+) macrophages and/or dendritic cells around areas of bacterial infection. CXCR3-dependent recruitment of cells to inflamed areas was critical for development of the CD103(-) population and pathogen clearance. Our studies have identified the 'preferential' development of CD103(-) TRM cells in inflammatory microenvironments within the lamina propria and suggest that this subset has a critical role in controlling infection.


Subject(s)
Antigens, CD/immunology , CD8-Positive T-Lymphocytes/immunology , Integrin alpha Chains/immunology , Intestinal Mucosa/immunology , Yersinia pseudotuberculosis Infections/immunology , Animals , Antigens, CD/genetics , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/microbiology , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/microbiology , CD8-Positive T-Lymphocytes/pathology , Cell Movement , Cellular Microenvironment , Dendritic Cells/immunology , Dendritic Cells/microbiology , Dendritic Cells/pathology , Gene Expression Regulation , Immunologic Memory , Immunophenotyping , Integrin alpha Chains/deficiency , Integrin alpha Chains/genetics , Intestinal Mucosa/microbiology , Intestinal Mucosa/pathology , Macrophages/immunology , Macrophages/microbiology , Macrophages/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, CXCR3/genetics , Receptors, CXCR3/immunology , Signal Transduction , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/immunology , Yersinia pseudotuberculosis/immunology , Yersinia pseudotuberculosis Infections/genetics , Yersinia pseudotuberculosis Infections/microbiology , Yersinia pseudotuberculosis Infections/pathology
2.
Nat Immunol ; 13(7): 667-73, 2012 May 27.
Article in English | MEDLINE | ID: mdl-22634866

ABSTRACT

T cell-specific deletion of the receptor for transforming growth factor-ß (TGF-ß) mediated by Cre recombinase expressed early in T cell development leads to early-onset lethal autoimmune disease that cannot be controlled by regulatory T cells. However, when we deleted that receptor through the use of Cre driven by a promoter that is active much later in T cell development, adult mice in which most peripheral CD4(+) or CD8(+) T cells lacked the receptor for TGF-ß showed no signs of autoimmunity. Because of their enhanced responses to weak stimulation of the T cell antigen receptor, when transferred into lymphopenic recipients, naive TGF-ß-unresponsive T cells underwent much more proliferation and differentiation into effector cells and induced lymphoproliferative disease. We propose that TGF-ß signaling controls the self-reactivity of peripheral T cells but that in the absence of TGF-ß signals, an added trigger such as lymphopenia is needed to drive overt autoimmune disease.


Subject(s)
Autoimmunity/immunology , Cell Proliferation , Lymphopenia/immunology , Signal Transduction/immunology , T-Lymphocytes/immunology , Transforming Growth Factor beta/immunology , Animals , Cells, Cultured , Female , Leukocyte Common Antigens/immunology , Lymphocyte Activation/immunology , Lymphoproliferative Disorders/immunology , Male , Mice , Receptors, Antigen, T-Cell/immunology , Receptors, Transforming Growth Factor beta/genetics , Receptors, Transforming Growth Factor beta/immunology
3.
Nat Immunol ; 12(6): 463-5, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21587308

ABSTRACT

Naive lymphocytes have a finite lifespan and are continually replaced by input from generative organs. In contrast, memory cells or their progeny can last a lifetime. The expanded populations of memory cells and their more widespread distribution provide protection against recurrent infection.


Subject(s)
B-Lymphocytes/immunology , Immunologic Memory/immunology , T-Lymphocytes/immunology , Vaccines/immunology , Animals , B-Lymphocytes/metabolism , Bacterial Infections/immunology , Cytokines/immunology , Cytokines/metabolism , Humans , Mice , Models, Immunological , T-Lymphocytes/metabolism , Virus Diseases/immunology
4.
Immunity ; 39(4): 687-96, 2013 Oct 17.
Article in English | MEDLINE | ID: mdl-24076049

ABSTRACT

Tissue-resident memory T (Trm) cells represent a population of memory CD8⁺ T cells that can act as first responders to local infection. The mechanisms regulating the formation and maintenance of intestinal Trm cells remain elusive. Here we showed that transforming growth factor-ß (TGF-ß) controlled both stages of gut Trm cell differentiation through different mechanisms. During the formation phase of Trm cells, TGF-ß signaling inhibited the migration of effector CD8⁺ T cells from the spleen to the gut by dampening the expression of integrin α4ß7. During the maintenance phase, TGF-ß was required for the retention of intestinal Trm cells at least in part through the induction of integrins αEß7 and α1, as well as CD69. Thus, the cytokine acts to control cytotoxic T cell differentiation in lymphoid and peripheral organs.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunologic Memory , Intestines/immunology , Lymphocytic Choriomeningitis/genetics , Signal Transduction/immunology , Spleen/immunology , Transforming Growth Factor beta/genetics , Adoptive Transfer , Animals , Antigens, CD/genetics , Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/genetics , Antigens, Differentiation, T-Lymphocyte/immunology , CD8-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/virology , Cell Movement , Gene Expression Regulation , Humans , Integrin alpha1/genetics , Integrin alpha1/immunology , Integrins/genetics , Integrins/immunology , Intestines/pathology , Intestines/virology , Lectins, C-Type/genetics , Lectins, C-Type/immunology , Lymphocytic Choriomeningitis/immunology , Lymphocytic Choriomeningitis/pathology , Lymphocytic Choriomeningitis/virology , Lymphocytic choriomeningitis virus/immunology , Mice , Mice, Transgenic , Spleen/pathology , Spleen/virology , Transforming Growth Factor beta/immunology
5.
Immunity ; 37(2): 235-48, 2012 Aug 24.
Article in English | MEDLINE | ID: mdl-22841161

ABSTRACT

The RIG-I-like receptors (RLRs) signal innate immune defenses upon RNA virus infection, but their roles in adaptive immunity have not been clearly defined. Here, we showed that the RLR LGP2 was not essential for induction of innate immune defenses, but rather was required for controlling antigen-specific CD8(+) T cell survival and fitness during peripheral T cell-number expansion in response to virus infection. Adoptive transfer and biochemical studies demonstrated that T cell-receptor signaling induced LGP2 expression wherein LGP2 operated to regulate death-receptor signaling and imparted sensitivity to CD95-mediated cell death. Thus, LGP2 promotes an essential prosurvival signal in response to antigen stimulation to confer CD8(+) T cell-number expansion and effector functions against divergent RNA viruses, including West Nile virus and lymphocytic choriomeningitis virus.


Subject(s)
Adaptive Immunity/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Survival/immunology , RNA Helicases/immunology , RNA, Viral/immunology , Animals , CD8-Positive T-Lymphocytes/metabolism , Cell Communication/immunology , Central Nervous System/immunology , Dendritic Cells/immunology , Humans , Immunity, Innate/immunology , Interferon-beta/immunology , Lymphocytic Choriomeningitis/immunology , Lymphocytic choriomeningitis virus/immunology , Macrophages/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Signal Transduction/immunology , West Nile Fever/immunology , West Nile virus/immunology , fas Receptor/immunology
6.
Immunity ; 35(2): 161-8, 2011 Aug 26.
Article in English | MEDLINE | ID: mdl-21867926

ABSTRACT

Resting naive CD8(+) T cells have an astounding capacity to react to pathogens by massive expansion and differentiation into cytotoxic effector cells that migrate to all corners of the body to clear the infection. The initial interaction with antigen-presenting cells in the central lymphoid organs drives an orchestrated program of differentiation aimed at producing sufficient numbers of effectors to get the job done without resulting in clonal exhaustion. Interactions with antigen-presenting cells and other immune cells continue at the site of infection to regulate further on-site expansion and differentiation, all with the goal of protecting the host with minimal bystander tissue damage. Here we review recent advances in CD8(+) T cell recognition of antigen in lymphoid as well as in nonlymphoid tissues in the periphery, and how CD8(+) T cell expansion and differentiation are controlled in these contexts.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cytokines/immunology , Histocompatibility Antigens Class I/immunology , Immune System/cytology , Lymphocyte Activation , Animals , Antigen Presentation , Cell Differentiation , Cell Movement , Cell Proliferation , Cytotoxicity, Immunologic , Homeostasis , Humans , Immune System/growth & development , Immunologic Memory , Th1-Th2 Balance
7.
J Virol ; 92(10)2018 05 15.
Article in English | MEDLINE | ID: mdl-29514902

ABSTRACT

The mouse model of West Nile virus (WNV), which is a leading cause of mosquito-borne encephalitis worldwide, has provided fundamental insights into the host and viral factors that regulate viral pathogenesis and infection outcome. In particular, CD8+ T cells are critical for controlling WNV replication and promoting protection against infection. Here, we present the characterization of a T cell receptor (TCR)-transgenic mouse with specificity for the immunodominant epitope in the WNV NS4B protein (here referred to as transgenic WNV-I mice). Using an adoptive-transfer model, we found that WNV-I CD8+ T cells behave similarly to endogenous CD8+ T cell responses, with an expansion phase in the periphery beginning around day 7 postinfection (p.i.) followed by a contraction phase through day 15 p.i. Through the use of in vivo intravascular immune cell staining, we determined the kinetics, expansion, and differentiation into effector and memory subsets of WNV-I CD8+ T cells within the spleen and brain. We found that red-pulp WNV-I CD8+ T cells were more effector-like than white-pulp WNV-I CD8+ T cells, which displayed increased differentiation into memory precursor cells. Within the central nervous system (CNS), we found that WNV-I CD8+ T cells were polyfunctional (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]), displayed tissue-resident characteristics (CD69+ and CD103+), persisted in the brain through day 15 p.i., and reduced the viral burden within the brain. The use of these TCR-transgenic WNV-I mice provides a new resource to dissect the immunological mechanisms of CD8+ T cell-mediated protection during WNV infection.IMPORTANCE West Nile Virus (WNV) is the leading cause of mosquito-borne encephalitis worldwide. There are currently no approved therapeutics or vaccines for use in humans to treat or prevent WNV infection. CD8+ T cells are critical for controlling WNV replication and protecting against infection. Here, we present a comprehensive characterization of a novel TCR-transgenic mouse with specificity for the immunodominant epitope in the WNV NS4B protein. In this study, we determine the kinetics, proliferation, differentiation into effector and memory subsets, homing, and clearance of WNV in the CNS. Our findings provide a new resource to dissect the immunological mechanisms of CD8+ T cell-mediated protection during WNV infection.


Subject(s)
Brain/immunology , CD8-Positive T-Lymphocytes/immunology , Viral Nonstructural Proteins/immunology , West Nile Fever/immunology , West Nile virus/immunology , Adoptive Transfer , Animals , Brain/virology , CD8-Positive T-Lymphocytes/cytology , Cell Differentiation/immunology , Cells, Cultured , Disease Models, Animal , Immunodominant Epitopes/immunology , Immunologic Memory/immunology , Interferon-gamma/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Tumor Necrosis Factor-alpha/immunology , Viral Load/immunology , West Nile Fever/virology
8.
Immunity ; 32(1): 79-90, 2010 Jan 29.
Article in English | MEDLINE | ID: mdl-20096607

ABSTRACT

Interleukin(IL)-2 and inflammation regulate effector and memory cytolytic T-lymphocyte (CTL) generation during infection. We demonstrate a complex interplay between IL-2 and inflammatory signals during CTL differentiation. IL-2 stimulation induced the transcription factor eomesodermin (Eomes), upregulated perforin (Prf1) transcription, and repressed re-expression of memory CTL markers Bcl6 and IL-7Ralpha. Binding of Eomes and STAT5 to Prf1 cis-regulatory regions correlated with transcriptional initiation (increased recruitment of RNA polymerase II to the Prf1 promoter). Inflammation (CpG, IL-12) enhanced expression of IL-2Ralpha and the transcription factor T-bet, but countered late Eomes and perforin induction while preventing IL-7Ralpha repression by IL-2. After infection of mice with lymphocytic choriomeningitis virus, IL-2Ralpha-deficient effector CD8(+) T cells expressed more Bcl6 but less perforin and granzyme B, formed fewer KLRG-1(+) and T-bet-expressing CTL, and killed poorly. Thus, inflammation influences both effector and memory CTL differentiation, whereas persistent IL-2 stimulation promotes effector at the expense of memory CTL development.


Subject(s)
Cell Differentiation/immunology , Gene Expression Regulation/immunology , Inflammation/immunology , Interleukin-2/immunology , T-Lymphocyte Subsets/cytology , T-Lymphocytes, Cytotoxic/cytology , Animals , Cell Differentiation/genetics , Cell Separation , Cytotoxicity, Immunologic/genetics , Cytotoxicity, Immunologic/immunology , Flow Cytometry , Gene Expression , Immunologic Memory/genetics , Immunologic Memory/immunology , Immunoprecipitation , Inflammation/metabolism , Interleukin-2/genetics , Interleukin-2/metabolism , Mice , Mice, Transgenic , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/genetics , Signal Transduction/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism , Transcription, Genetic
9.
Immunity ; 28(4): 533-45, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18356084

ABSTRACT

Requirements for CD4+ T cell memory differentiation were analyzed with adoptively transferred SMARTA T cell receptor (TCR) transgenic cells specific for alymphocytic choriomeningitis virus (LCMV) epitope. LCMV-induced effector and memory differentiation of SMARTA cells mimicked the endogenous CD4+ T cell response. In contrast, infection with a recombinant Listeria expressing the LCMV epitope, although resulting initially in massive SMARTA expansion, led to loss of effector function and rapid cell death characterized by high expression of the apoptosis regulator Bim. Defective memory differentiation was seen after stimulation of naive but not memory SMARTA cells, was independent of precursor frequency, and correlated with a lower TCR avidity compared to endogenous responders. In addition, long-lived endogenous CD4+ memory T cells skewed to a higher functional avidity over time. These results support a model in which CD4+ T cell memory differentiation and longevity depend on the strength of the TCR signal during the primary response.


Subject(s)
CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , Cell Differentiation/immunology , Immunologic Memory , Amino Acid Sequence , Animals , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/transplantation , Cell Adhesion/genetics , Cell Adhesion/immunology , Cell Differentiation/genetics , Cell Line , Cell Proliferation , Chlorocebus aethiops , Cricetinae , Immunologic Memory/genetics , Interferon-gamma/biosynthesis , Interleukin-2/biosynthesis , Listeria monocytogenes/immunology , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Lymphocytic choriomeningitis virus/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Molecular Sequence Data , Tumor Necrosis Factor-alpha/biosynthesis , Vero Cells
10.
J Immunol ; 195(1): 41-5, 2015 Jul 01.
Article in English | MEDLINE | ID: mdl-25980012

ABSTRACT

Inflammatory caspases, including caspase-11, are upregulated in CD8(+) T cells after Ag-specific activation, but little is known about their function in T cells. We report that caspase-11-deficient (Casp11(-/-)) T cells proliferated more readily in response to low-affinity and low-abundance ligands both in vitro and in vivo due to an increased ability to signal through the TCR. In addition to increased numbers, Casp11(-/-) T cells had enhanced effector function compared with wild-type cells, including increased production of IL-2 and reduced expression of CD62L. Casp11(-/-) T cells specific for endogenous Ags were more readily deleted than wild-type cells. These data indicate that caspase-11 negatively regulates TCR signaling, possibly through its ability to regulate actin polymerization, and inhibiting its activity could enhance the expansion and function of low-affinity T cells.


Subject(s)
Antigens/immunology , CD8-Positive T-Lymphocytes/immunology , Caspases/immunology , Gene Expression Regulation, Developmental , Receptors, Antigen, T-Cell/immunology , Animals , CD8-Positive T-Lymphocytes/pathology , Caspases/deficiency , Caspases/genetics , Caspases, Initiator , Cell Proliferation , Immunity, Innate , Interleukin-2/genetics , Interleukin-2/immunology , L-Selectin/genetics , L-Selectin/immunology , Listeria monocytogenes/chemistry , Listeria monocytogenes/immunology , Mice , Mice, Knockout , Ovalbumin/immunology , Receptors, Antigen, T-Cell/genetics , Signal Transduction
11.
J Immunol ; 194(5): 2260-7, 2015 Mar 01.
Article in English | MEDLINE | ID: mdl-25609844

ABSTRACT

The study of T cell immunity at barrier surfaces has largely focused on T cells bearing the αß TCR. However, T cells that express the γδ TCR are disproportionately represented in peripheral tissues of mice and humans, suggesting they too may play an important role responding to external stimuli. In this article, we report that, in a murine model of cutaneous infection with vaccinia virus, dermal γδ T cell numbers increased 10-fold in the infected ear and resulted in a novel γδ T cell population not found in naive skin. Circulating γδ T cells were specifically recruited to the site of inflammation and differentially contributed to dermal populations based on their CD27 expression. Recruited γδ T cells, the majority of which were CD27(+), were granzyme B(+) and made up about half of the dermal population at the peak of the response. In contrast, recruited and resident γδ T cell populations that made IL-17 were CD27(-). Using a double-chimera model that can discriminate between the resident dermal and recruited γδ T cell populations, we demonstrated their divergent functions and contributions to early stages of tissue inflammation. Specifically, the loss of the perinatal thymus-derived resident dermal population resulted in decreased cellularity and collateral damage in the tissue during viral infection. These findings have important implications for our understanding of immune coordination at barrier surfaces and the contribution of innate-like lymphocytes on the front lines of immune defense.


Subject(s)
Dermis/immunology , Ear/virology , Poxviridae Infections/immunology , Receptors, Antigen, T-Cell, gamma-delta/immunology , T-Lymphocyte Subsets/immunology , Vaccinia virus/immunology , Animals , Cell Movement , Chimera/immunology , Chimera/virology , Dermis/pathology , Dermis/virology , Ear/pathology , Gene Expression Regulation , Granzymes/genetics , Granzymes/immunology , Immunity, Innate , Interleukin-17/genetics , Interleukin-17/immunology , Lymph Nodes/immunology , Lymph Nodes/pathology , Lymph Nodes/virology , Mice , Mice, Inbred C57BL , Mice, Knockout , Poxviridae Infections/pathology , Poxviridae Infections/virology , Receptors, Antigen, T-Cell, gamma-delta/genetics , Signal Transduction , Spleen/immunology , Spleen/pathology , Spleen/virology , T-Lymphocyte Subsets/pathology , T-Lymphocyte Subsets/virology , Thymus Gland/immunology , Thymus Gland/pathology , Thymus Gland/virology , Tumor Necrosis Factor Receptor Superfamily, Member 7/genetics , Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology
12.
Nature ; 471(7340): 629-32, 2011 Mar 31.
Article in English | MEDLINE | ID: mdl-21455179

ABSTRACT

After an infection, cytotoxic T lymphocyte precursors proliferate and become effector cells by recognizing foreign peptides in the groove of major histocompatibility complex (MHC) class I molecules expressed by antigen-presenting cells (APCs). Professional APCs specialized for T-cell activation acquire viral antigen either by becoming infected themselves (direct presentation) or by phagocytosis of infected cells, followed by transfer of antigen to the cytosol, processing and MHC class I loading in a process referred to as cross-presentation. An alternative way, referred to as 'cross-dressing', by which an uninfected APC could present antigen was postulated to be by the transfer of preformed peptide-MHC complexes from the surface of an infected cell to the APC without the need of further processing. Here we show that this mechanism exists and boosts the antiviral response of mouse memory CD8(+) T cells. A number of publications have demonstrated sharing of peptide-loaded MHC molecules in vitro. Our in vitro experiments demonstrate that cross-dressing APCs do not acquire peptide-MHC complexes in the form of exosomes released by donor cells. Rather, the APCs and donor cells have to contact each other for the transfer to occur. After a viral infection, we could isolate cross-dressed APCs able to present viral antigen in vitro. Furthermore, using the diphtheria toxin system to selectively eliminate APCs that could only acquire viral peptide-MHC complexes by cross-dressing, we show that such presentation can promote the expansion of resting memory T cells. Notably, naive T cells were excluded from taking part in the response. Cross-dressing is a mechanism of antigen presentation used by dendritic cells that may have a significant role in activating previously primed CD8(+) T cells.


Subject(s)
Antigen Presentation/immunology , CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Immunologic Memory/immunology , Lymphocyte Activation/immunology , Models, Immunological , Virus Diseases/immunology , Animals , Antigens, Viral/immunology , CD8-Positive T-Lymphocytes/cytology , Cell Adhesion , Cell Proliferation , Cells, Cultured , Dendritic Cells/cytology , Dendritic Cells/metabolism , Diphtheria Toxin , Exosomes , Female , H-2 Antigens/immunology , H-2 Antigens/metabolism , Immunological Synapses , Lymphocytic choriomeningitis virus/immunology , Lymphocytic choriomeningitis virus/physiology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Protein Transport , Vesiculovirus/immunology , Vesiculovirus/physiology , Virus Diseases/virology
13.
Proc Natl Acad Sci U S A ; 111(19): 7066-71, 2014 May 13.
Article in English | MEDLINE | ID: mdl-24785297

ABSTRACT

Folliculin-interacting protein 1 (Fnip1) is an adaptor protein that physically interacts with AMPK, an energy-sensing kinase that stimulates mitochondrial biogenesis and autophagy in response to low ATP, while turning off energy consumption mediated by mammalian target of rapamycin. Previous studies with Fnip1-null mice revealed that Fnip1 is essential for pre-B-cell development. Here we report a critical role of Fnip1 in invariant natural killer T (iNKT) cell development. Thymic iNKT development in Fnip1(-/-) mice was arrested at stage 2 (NK1.1(-)CD44(+)) but development of CD4, CD8, γδ T-cell, and NK cell lineages proceeded normally. Enforced expression of a Vα14Jα18 iNKT TCR transgene or loss of the proapoptotic protein Bim did not rescue iNKT cell maturation in Fnip1(-/-) mice. Whereas most known essential transcription factors for iNKT cell development were represented normally, Fnip1(-/-) iNKT cells failed to down-regulate Promyelocytic leukemia zinc finger compared with their WT counterparts. Moreover, Fnip1(-/-) iNKT cells contained hyperactive mTOR and reduced mitochondrial number despite lower ATP levels, resulting in increased sensitivity to apoptosis. These results indicate that Fnip1 is vital for iNKT cell development by maintaining metabolic homeostasis in response to metabolic stress.


Subject(s)
Carrier Proteins/immunology , Carrier Proteins/metabolism , Energy Metabolism/immunology , Natural Killer T-Cells/immunology , Natural Killer T-Cells/metabolism , Adenosine Triphosphate/metabolism , Animals , Birt-Hogg-Dube Syndrome/immunology , Birt-Hogg-Dube Syndrome/metabolism , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Carrier Proteins/genetics , Cell Survival/immunology , Female , Homeostasis/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Natural Killer T-Cells/cytology , Receptors, Antigen, T-Cell, gamma-delta/immunology , Receptors, Antigen, T-Cell, gamma-delta/metabolism , TOR Serine-Threonine Kinases/immunology , TOR Serine-Threonine Kinases/metabolism , Thymus Gland/cytology , Thymus Gland/immunology
14.
J Immunol ; 192(1): 200-5, 2014 Jan 01.
Article in English | MEDLINE | ID: mdl-24273000

ABSTRACT

Generating a diverse T cell memory population through vaccination is a promising strategy to overcome pathogen epitope variability and tolerance to tumor Ags. The effector and memory pool becomes broad in TCR diversity by recruiting high- and low-affinity T cells. We wanted to determine which factors dictate whether a memory T cell pool has a broad versus focused repertoire. We find that inflammation increases the magnitude of low- and high-affinity T cell responses equally well, arguing against a synergistic effect of TCR and inflammatory signals on T cell expansion. We dissect the differential effects of TCR signal strength and inflammation and demonstrate that they control effector T cell survival in a bim-dependent manner. Importantly, bim-dependent cell death is overcome with a high Ag dose in the context of an inflammatory environment. Our data define the framework for the generation of a broad T cell memory pool to inform future vaccine design.


Subject(s)
Apoptosis Regulatory Proteins/metabolism , Inflammation/immunology , Inflammation/metabolism , Membrane Proteins/metabolism , Proto-Oncogene Proteins/metabolism , Receptors, Antigen, T-Cell/metabolism , Signal Transduction , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Animals , Apoptosis Regulatory Proteins/genetics , Bcl-2-Like Protein 11 , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cell Death/genetics , Cell Death/immunology , Immunologic Memory/genetics , Membrane Proteins/genetics , Mice , Mice, Transgenic , Proto-Oncogene Proteins/genetics
15.
Proc Natl Acad Sci U S A ; 110(15): 6055-60, 2013 Apr 09.
Article in English | MEDLINE | ID: mdl-23530242

ABSTRACT

Development of an antimalarial subunit vaccine inducing protective cytotoxic T lymphocyte (CTL)-mediated immunity could pave the way for malaria eradication. Experimental immunization with sporozoites induces this type of protective response, but the extremely large number of proteins expressed by Plasmodium parasites has so far prohibited the identification of sufficient discrete T-cell antigens to develop subunit vaccines that produce sterile immunity. Here, using mice singly immunized with Plasmodium yoelii sporozoites and high-throughput screening, we identified a unique CTL response against the parasite ribosomal L3 protein. Unlike CTL responses to the circumsporozoite protein (CSP), the population of L3-specific CTLs was not expanded by multiple sporozoite immunizations. CSP is abundant in the sporozoite itself, whereas L3 expression does not increase until the liver stage. The response induced by a single immunization with sporozoites reduces the parasite load in the liver so greatly during subsequent immunizations that L3-specific responses are only generated during the primary exposure. Functional L3-specific CTLs can, however, be expanded by heterologous prime-boost regimens. Thus, although repeat sporozoite immunization expands responses to preformed antigens like CSP that are present in the sporozoite itself, this immunization strategy may not expand CTLs targeting parasite proteins that are synthesized later. Heterologous strategies may be needed to increase CTL responses across the entire spectrum of Plasmodium liver-stage proteins.


Subject(s)
Plasmodium yoelii/immunology , Protozoan Proteins/immunology , Sporozoites/immunology , T-Lymphocytes/immunology , Animals , CD8-Positive T-Lymphocytes/immunology , Cell Separation , Enzyme-Linked Immunosorbent Assay , Epitopes/immunology , Immunization , Immunophenotyping , Interferon-gamma/metabolism , Malaria Vaccines/immunology , Mice , Mice, Inbred BALB C , Peptides/immunology , Protozoan Proteins/metabolism , Sequence Analysis, DNA , T-Lymphocytes/parasitology
16.
Eur J Immunol ; 44(7): 1936-46, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24723377

ABSTRACT

We used a newly generated T-cell receptor mimic monoclonal antibody (TCRm MAb) that recognizes a known nonself immunodominant peptide epitope from West Nile virus (WNV) NS4B protein to investigate epitope presentation after virus infection in C57BL/6 mice. Previous studies suggested that peptides of different length, either SSVWNATTAI (10-mer) or SSVWNATTA (9-mer) in complex with class I MHC antigen H-2D(b) , were immunodominant after WNV infection. Our data establish that both peptides are presented on the cell surface after WNV infection and that CD8(+) T cells can detect 10- and 9-mer length variants similarly. This result varies from the idea that a given T-cell receptor (TCR) prefers a single peptide length bound to its cognate class I MHC. In separate WNV infection studies with the TCRm MAb, we show that in vivo the 10-mer was presented on the surface of uninfected and infected CD8α(+) CD11c(+) dendritic cells, which suggests the use of direct and cross-presentation pathways. In contrast, CD11b(+) CD11c(-) cells bound the TCRm MAb only when they were infected. Our study demonstrates that TCR recognition of peptides is not limited to certain peptide lengths and that TCRm MAbs can be used to dissect the cell-type specific mechanisms of antigen presentation in vivo.


Subject(s)
Dendritic Cells/immunology , Immunodominant Epitopes , Receptors, Antigen, T-Cell/physiology , West Nile virus/immunology , Animals , CD11b Antigen/analysis , CD11c Antigen/analysis , CD8-Positive T-Lymphocytes/immunology , Mice , Mice, Inbred C57BL , Viral Nonstructural Proteins/immunology
17.
Nature ; 458(7235): 211-4, 2009 Mar 12.
Article in English | MEDLINE | ID: mdl-19182777

ABSTRACT

After an infection, T cells that carry the CD8 marker are activated and undergo a characteristic kinetic sequence of rapid expansion, subsequent contraction and formation of memory cells. The pool of naive T-cell clones is diverse and contains cells bearing T-cell antigen receptors (TCRs) that differ in their affinity for the same antigen. How these differences in affinity affect the function and the response kinetics of individual T-cell clones was previously unknown. Here we show that during the in vivo response to microbial infection, even very weak TCR-ligand interactions are sufficient to activate naive T cells, induce rapid initial proliferation and generate effector and memory cells. The strength of the TCR-ligand interaction critically affects when expansion stops, when the cells exit lymphoid organs and when contraction begins; that is, strongly stimulated T cells contract and exit lymphoid organs later than weakly stimulated cells. Our data challenge the prevailing view that strong TCR ligation is a prerequisite for CD8(+) T-cell activation. Instead, very weak interactions are sufficient for activation, but strong TCR ligation is required to sustain T-cell expansion. We propose that in response to microbial challenge, T-cell clones with a broad range of avidities for foreign ligands are initially recruited, and that the pool of T cells subsequently matures in affinity owing to the more prolonged expansion of high-affinity T-cell clones.


Subject(s)
Antibody Affinity/immunology , Antigens, Bacterial/immunology , T-Lymphocytes/immunology , Animals , CD8-Positive T-Lymphocytes/immunology , Cell Movement/immunology , Immunologic Memory/immunology , Ligands , Listeria monocytogenes/immunology , Listeriosis/immunology , Mice , Mice, Inbred C57BL
18.
J Immunol ; 189(7): 3462-71, 2012 Oct 01.
Article in English | MEDLINE | ID: mdl-22922816

ABSTRACT

Tissue resident memory (Trm) CD8 T cells represent a newly described memory T cell population. We have previously characterized a population of Trm cells that persists within the brain after acute virus infection. Although capable of providing marked protection against a subsequent local challenge, brain Trm cells do not undergo recall expansion after dissociation from the tissue. Furthermore, these Trm cells do not depend on the same survival factors as the circulating memory T cell pool as assessed either in vivo or in vitro. To gain greater insight into this population of cells, we compared the gene expression profiles of Trm cells isolated from the brain with those of circulating memory T cells isolated from the spleen after an acute virus infection. Trm cells displayed altered expression of genes involved in chemotaxis, expressed a distinct set of transcription factors, and overexpressed several inhibitory receptors. Cumulatively, these data indicate that Trm cells are a distinct memory T cell population disconnected from the circulating memory T cell pool and display a unique molecular signature that likely results in optimal survival and function within their local environment.


Subject(s)
Antigens, CD/biosynthesis , Antigens, CD/genetics , Brain/cytology , Brain/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Immunologic Memory , Integrin alpha Chains/biosynthesis , Integrin alpha Chains/genetics , Animals , Antigens, CD/blood , Brain/metabolism , CD8-Positive T-Lymphocytes/cytology , Cell Separation , Cells, Cultured , Humans , Immunologic Memory/genetics , Immunophenotyping , Integrin alpha Chains/blood , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Organ Specificity/genetics , Organ Specificity/immunology , T Cell Transcription Factor 1/biosynthesis , T Cell Transcription Factor 1/blood , T Cell Transcription Factor 1/genetics , T-Box Domain Proteins/biosynthesis , T-Box Domain Proteins/blood , T-Box Domain Proteins/genetics , Vesicular Stomatitis/immunology , Vesicular Stomatitis/metabolism , Vesicular Stomatitis/pathology , Vesicular stomatitis Indiana virus/immunology
19.
J Exp Med ; 204(8): 1803-12, 2007 Aug 06.
Article in English | MEDLINE | ID: mdl-17664293

ABSTRACT

An optimal CD8(+) T cell response requires signals from the T cell receptor (TCR), co-stimulatory molecules, and cytokines. In most cases, the relative contribution of these signals to CD8(+) T cell proliferation, accumulation, effector function, and differentiation to memory is unknown. Recent work (Boyman, O., M. Kovar, M.P. Rubinstein, C.D. Surh, and J. Sprent. 2006. Science. 311:1924-1927; Kamimura, D., Y. Sawa, M. Sato, E. Agung, T. Hirano, and M. Murakami. 2006. J. Immunol. 177:306-314) has shown that anti-interleukin (IL) 2 monoclonal antibodies that are neutralizing in vitro enhance the potency of IL-2 in vivo. We investigated the role of IL-2 signals in driving CD8(+) T cell proliferation in the absence of TCR stimulation by foreign antigen. IL-2 signals induced rapid activation of signal transducer and activator of transcription 5 in all CD8(+) T cells, both naive and memory phenotype, and promoted the differentiation of naive CD8(+) T cells into effector cells. IL-2-anti-IL-2 complexes induced proliferation of naive CD8(+) T cells in an environment with limited access to self-major histocompatibility complex (MHC) and when competition for self-MHC ligands was severe. After transfer into wild-type animals, IL-2-activated CD8(+) T cells attained and maintained a central memory phenotype and protected against lethal bacterial infection. IL-2-anti-IL-2 complex-driven memory-like CD8(+) T cells had incomplete cellular fitness compared with antigen-driven memory cells regarding homeostatic turnover and cytokine production. These results suggest that intense IL-2 signals, with limited contribution from the TCR, program the differentiation of protective memory-like CD8(+) cells but are insufficient to guarantee overall cellular fitness.


Subject(s)
CD8-Positive T-Lymphocytes/cytology , Immunologic Memory , Interleukin-2/antagonists & inhibitors , Interleukin-2/metabolism , Adoptive Transfer , Animals , CD8-Positive T-Lymphocytes/metabolism , Cell Differentiation , Cell Proliferation , Ligands , Lymphocyte Activation , Major Histocompatibility Complex , Mice , Models, Biological , Phenotype , Receptors, Antigen, T-Cell/metabolism , STAT5 Transcription Factor/metabolism
20.
J Exp Med ; 204(9): 2159-69, 2007 Sep 03.
Article in English | MEDLINE | ID: mdl-17709423

ABSTRACT

Mycobacterium tuberculosis (Mtb) frequently establishes persistent infections that may be facilitated by mechanisms that dampen immunity. T regulatory (T reg) cells, a subset of CD4(+) T cells that are essential for preventing autoimmunity, can also suppress antimicrobial immune responses. We use Foxp3-GFP mice to track the activity of T reg cells after aerosol infection with Mtb. We report that during tuberculosis, T reg cells proliferate in the pulmonary lymph nodes (pLNs), change their cell surface phenotype, and accumulate in the pLNs and lung at a rate parallel to the accumulation of effector T cells. In the Mtb-infected lung, T reg cells accumulate in high numbers in all sites where CD4(+) T cells are found, including perivascular/peribronchiolar regions and within lymphoid aggregates of granulomas. To determine the role of T reg cells in the immune response to tuberculosis, we generated mixed bone marrow chimeric mice in which all cells capable of expressing Foxp3 expressed Thy1.1. When T reg cells were depleted by administration of anti-Thy1.1 before aerosol infection with Mtb, we observed approximately 1 log less of colony-forming units of Mtb in the lungs. Thus, after aerosol infection, T reg cells proliferate and accumulate at sites of infection, and have the capacity to suppress immune responses that contribute to the control of Mtb.


Subject(s)
Forkhead Transcription Factors/metabolism , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/immunology , Tuberculosis/immunology , Animals , Biomarkers/metabolism , Bone Marrow Cells/cytology , Cell Movement , Cell Proliferation , Chimera , Colony Count, Microbial , Granuloma/immunology , Granuloma/pathology , Interleukin-10/biosynthesis , Lung/microbiology , Lung/pathology , Lymph Nodes/immunology , Lymph Nodes/pathology , Mice , Mice, Inbred C57BL , Mycobacterium tuberculosis/isolation & purification , Phenotype , Up-Regulation/genetics
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