T cell & Rui He 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

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