Transcript Types of cell-mediated immune reactions

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
 Effector mechanisms of cell-mediated immunity
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
Different types of microbes elicit distinct protective T
cell responses
 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
Defects in CMI result in increased susceptibility to infection by viruses
and intracellular bacteria
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
The differentiation of CD4+Th cell subsets
The subsets of CD4+Th cells
 How they are induced,
 What cytokines they produce
 What effector mechanisms they activate
Properties of CD4+ Th1 and Th2 subsets
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
 IL-12
 IFN-
 IL-18
 type I IFNs (in human)
 Important transcription factors (TF) for the Th1 differentiation
 T-bet: master regulator
 STAT4
 STAT1
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-
Ag recognition by TCR
STAT-1
T-bet
A positive amplification loop between T-bet and IFN-
Differentiation of Th1 subsets
Differentiation of Th2 Subset
 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
 Important TF for the Th2 differentiation
 GATA-3: master regulator
 STAT6
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
Ag recognition by TCR
STAT-6
GATA-3
GATA-3
A master regulator of Th2 differentiation
 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
Development of Th2 subsets
Development of Th1 and Th2 subsets
Stimuli that influence the pattern of Th cell differentiation
 Cytokines
 High doses of antigen without adjuvants
 Different subsets of dendritic cells may exist
 The genetic makeup of the host
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
Effector functions of Th1 cells
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
T cell signals that activate macrophages
 IFN-
 CD40L-CD40 interactions
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
The effector functions of activated macrophages
 Killing of phagocytosed microbes
 Stimulation of acute inflammation
 Tissue Repair
 Become the more efficient APCs
Activation and functions of macrophages in CMI
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
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
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
Effector functions of Th2 cells
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
The Th17 Subset
Th17-Mediated Immune Responses
 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
Cytotoxic T Lymphocytes (CTLs)
Effector CD8+ T Cells
Eliminate intracellular microbes mainly by killing infected cells
CTL-mediated cytotoxcity
 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
Immune synapse between CTLs and a target cell
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
Steps in CTL-mediated lysis of target cells
Recognition of Antigen and Activation of CTLs
Recognition of Antigen and Activation of CTLs
Mechanisms of CTL-mediated lysis of target cells
 Fas/FasL pathway
 Granule exocytosis
The two important granule proteins for CTL killing
function
 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.
Mechanisms of CTL-mediated lysis of target cells
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