T cell & Rui He [email protected] Department of Immunology Shanghai Medical School Fudan University T cell-mediated immunity.

T cell &

Rui He

[email protected]

Department of Immunology

Shanghai Medical School

Fudan University

T cell-mediated immunity

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

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

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

Important transcription factors (TF) for the Th1 differentiation

IL-12

IFN-

IL-18

type I IFNs (in human)

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- STAT-1

Ag recognition by TCR T-bet

A positive amplification loop between T-bet and IFN-

Differentiation of Th1 subsets

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

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

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

Development of Th2 subsets

Development of Th1 and Th2 subsets

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

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

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

Cytotoxic T Lymphocytes (CTLs)

Effector CD8+ T Cells

Eliminate intracellular microbes mainly by killing infected cells

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

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

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

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