t cell &
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T cell &. T cell-mediated immunity. Rui He [email protected] Department of Immunology Shanghai Medical School Fudan University. Types of adaptive immune responses. Agenda. Types of cell-mediated immune reactions The differentiation of CD4+Th cell subsets - PowerPoint PPT PresentationTRANSCRIPT
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T cell &
Rui He
Department of Immunology
Shanghai Medical School
Fudan University
T cell-mediated immunity
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Types of adaptive immune responses
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Agenda
Types of cell-mediated immune reactions
The differentiation of CD4+Th cell subsets
Effector mechanisms of cell-mediated immunity
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Types of cell-mediated immune reactions
CD4+ Th responses
CD8+ CTL responses
Delayed-type Hypersensitivity (DTH)
T cell-dependent immune reactions that cause normal tissues injury
NK cell mediated
innate immunity, kill infected cell early
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CD4+ Th1 responses
microbes residing within the phagosomes of phagocytes
CD8+ CTL responses
microbes residing in the cytoplasm of various cell types
CD4+ Th2 responses
helminthic parasites
Different types of microbes elicit distinct protective T cell responses
Defects in CMI result in increased susceptibility to infection by viruses and intracellular bacteria
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Cell-mediated immune responses
The development of effector T cells
Migration of effector T cells and other leukocytes to sites
of infection
Effector functions to eliminate microbes
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The differentiation of CD4+Th cell subsets
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The subsets of CD4+Th cells
How they are induced, What cytokines they produce What effector mechanisms they activate
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Properties of CD4+ Th1 and Th2 subsets
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Differentiation of Th1 Subset Stimulated by intracellular microbes that infect or activate
macrophages or NK cells
Listeria, mycobacteria and Leishmania
Important cytokines for the Th1 differentiation
Important transcription factors (TF) for the Th1 differentiation
IL-12
IFN-
IL-18
type I IFNs (in human)
T-bet: master regulator
STAT4
STAT1
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The molecular basis of Th1 differentiation
The interplay of signals from the T cell receptor, the cytokines IFN- and IL-12, and the TF T-bet, STAT1, and STAT4
IL-12 STAT-4
IFN- STAT-1
Ag recognition by TCR T-bet
A positive amplification loop between T-bet and IFN-
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Differentiation of Th1 subsets
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Differentiation of Th2 Subset
Important TF for the Th2 differentiation
Stimulated by microbes and antigens that cause persistent or repeated
T cell stimulation with little inflammation or macrophage activation
Helminth and allergens
Important cytokines for the Th1 differentiation
IL-4
GATA-3: master regulator
STAT6
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The molecular basis of Th2 differentiation
The interplay of signals from the T cell receptor, the cytokine IL-4, and the TF GATA-3 and STAT6
Th2 differentiation is dependent on IL-4
IL-4 STAT-6
Ag recognition by TCR GATA-3
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GATA-3
Enhances expression of the Th2 cytokine genes IL-4, IL-5, and IL-13 by
1) directly interacting with the promoters of these genes
2) causing chromatin remodeling
Enhances its own expression via a positive feedback loop
Blocks Th1 differentiation
A master regulator of Th2 differentiation
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Development of Th2 subsets
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Development of Th1 and Th2 subsets
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Cytokines
Stimuli that influence the pattern of Th cell differentiation
High doses of antigen without adjuvants
Different subsets of dendritic cells may exist
The genetic makeup of the host
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Th1-Mediated Immune Responses
The physiological role of Th1 cells
phagocyte-mediated defense against infections, especially with
intracellular microbes
Pathological roles of Th1 cell
Many organ-specific autoimmune diseases and inflammatory reactions
are due to excessive activation of Th1 cells
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Effector functions of Th1 cells
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IFN-
The major sources: Th1, CD8+ T cells
The major macrophage-activating cytokine
Stimulates the microbicidal activities of phagocytes
Stimulates the production of IgG Abs to promote the
phagocytosis of microbes
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T cell signals that activate macrophages
IFN-
CD40L-CD40 interactions
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CD40L/CD40
Deliever contact-mediated signals
activates the transcription factors nuclear factor κB (NF-κB) and activation protein-1 (AP-1)
Clinical evidence
Humans with inherited mutations in CD40L
(X-linked hyper-IgM syndrome) :
severe deficiencies in CMI to intracellular microbes
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The effector functions of activated macrophages
Killing of phagocytosed microbes
Stimulation of acute inflammation
Tissue Repair
Become the more efficient APCs
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Activation and functions of macrophages in CMI
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The development of Chronic DTH reactions
When a Th1 response to an infection activates macrophages but fails to eradicate phagocytosed microbes.
Fibrosis is a hallmark of chronic DTH reactions
The mechanism of tissue damage in several autoimmune diseases
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Th2-Mediated Immune Responses
The physiological role of Th2 cells
Elimination of helminthic infection
Pathological roles of Th2 cell
The underlying cause of allergic reactions
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Effector functions of Th2 cells
Promotion of antigen-specific IgE production
Activation of eosinophils and mast cells
Alternative macrophage activation
Barrier immunity by Th2 cytokine
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Effector functions of Th2 cells
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The effector function of Th2 cytokines
IL-4 and IL-13
Stimulate the production of antigen-specific IgE
Alternatively activate macrophages
IL-4 promotes expulsion of microbes while IL-13 stimulates mucus
secretion
IL-5 Recruit and activate eosinophils
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The Th17 Subset
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The physiological role of Th17 cells
Protection against extracellular bacterial and fungal infections
Pathological roles of Th17 cell
may be important in meditating tissue damage in immune-mediated
inflammatory diseases, e.g. autoimmune diseases
Th17-Mediated Immune Responses
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Cytotoxic T Lymphocytes (CTLs)
Effector CD8+ T Cells
Eliminate intracellular microbes mainly by killing infected cells
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Antigen specific
Only kill targets that express the same class I-associated
antigen that triggered their differentiation from naïve CD8+ T cell
Contact dependent
The formation of immunological synapse
the specific delivery of the molecules
CTL-mediated cytotoxcity
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Immune synapse between CTLs and a target cell
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Steps in CTL-mediated lysis of target cells
antigen recognition,
activation of the CTLs,
delivery of the "lethal hit" that kills the target cells,
release of the CTLs from target cell
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Steps in CTL-mediated lysis of target cells
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Recognition of Antigen and Activation of CTLs
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Recognition of Antigen and Activation of CTLs
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Mechanisms of CTL-mediated lysis of target cells
Fas/FasL pathway
Granule exocytosis
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Perforin
a pore-forming protein molecule
Main function is to facilitate delivery of the granzymes into the
cytosol of the target cell
Granzymes (granule enzymes)
Serine proteases, including A. B.C
Granzymes B initiate apoptotic pathways involve caspases.
The two important granule proteins for CTL killing function
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Mechanisms of CTL-mediated lysis of target cells
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Release of CTL from its target cell
Usually occurs even before the target cell goes on to die
May facilitated by decreased affinity of accessory
molecules for their ligands