CMI Functions of TH Cells, TH1 and TH2 Cells, Macrophages, Tc Cells, and NK Cells; Immunoregulation

Critical Role of TH Cells in Specific Immunity Select effector mechanisms Induce proliferation in appropriate effectors Enhance functional activities of effectors

B cell TH Tc cell NK NK cell Ag APC Antigen-presenting cell Ag Ag Ag B cell TH cell Cytokines Tc cell Granulocyte Macrophage NK NK cell Cytokines

T Cell-B Cell Interactions (hapten-carrier effect) TH cells recognize carrier APC B cells recognize hapten (Soluble Ag) TH and B cells cooperate by interacting Interactions are class II self-MHC restricted

Uniqueness of B Cells Express both immunoglobulin (Ig) and class II MHC on cell surface Capable of producing antibody of same specificity as that of its surface Ig AND Capable of functioning as an antigen presenting cell

Mechanism of Hapten-Carrier Hapten recognized by Ig receptor on B cell Hapten-carrier endocytosed Carrier processed and presented on class II MHC to TH cell Activated TH cell produces cytokines Cytokines enable B cell to be activated to produce anti-hapten antibodies

1. Antigen presentation to B7 CD28 TCR T helper cell B CD40 Immunoglobulin receptor MHC II Cytokine receptor B cell 1. Antigen presentation to TH cell 2. B7 expressed 3. Th cell is activated and expresses CD40 ligand, Cytokines secreted 4. Cytokine binds to cytokine receptor, CD40 ligand binds to CD40 B cell CD40 ligand B cell T helper 5. B cell activated 6. B cells proliferate, differentiate, secrete Ig Cytokine

Th cells are primed by antigen-presenting cell Class II MHC APC B cell Th cells are primed by antigen-presenting cell B cell takes up and presents antigen TH cell B cell B-T cell cooperation B cells receive signals from T cells B cell B cell B cells divide B cell Antibody forming memory

B Cells In Secondary Responses Memory cells created during primary response Have high-affinity Ig receptors Can therefore take up antigens at much lower concentrations than other antigen presenting cells that lack Ig antigen receptors

Naïve TH Cells Can Differentiate Into TH1 or TH2 Cells Naive TH cells Short-term stimulation Chronic stimulation Long term Memory cells IFNγ IL-2 TH1 cell IL-12 THP cell THO cell THM cell TH2 cell IL-4 IL-2 IFNγ IL-2 IL-4 IL-5 IL-10 IL-2 IL-4 IL-5 IL-6 IL-10

Functions of TH1 and TH2 Cells Macrophage B cell IFNγ Activates IL-4 IL-5 IL-10 Inhibits production Inhibits proliferation Mast cell Eosinophil Antibodies (including IgE)

Cytokines Regulate Ig Class Switching Fc region of antibodies determines effector function in different anatomical locations Class (isotype) switching produces class or subclass of antibody most effective in host defense Cytokines acting alone or in combination regulate class switching

Central Role of Macrophages in Natural and Specific Immunity Involved in initial defense and antigen presentation and have effector functions Macrophage TH cell Cytokines Lymphokines Anti-microbial functions Anti-tumor functions Activate Invading agent Antigen presentation Activated macrophage

Macrophage Activation Macrophage activation results from alterations in gene products that govern new functions. Two major mechanisms that activate macrophages: IFN-γ produced by TH or TH1 cells plus bacterial endotoxin (LPS) IFN-γ produced by TH or TH1 cells plus TNF-α

Mechanism of Macrophage Activation Activated Macrophage Bacterial endotoxin (lipopolysaccharide) triggers cytokine production TH1 cell 1 IFN gamma 2 TNF alpha Various products

Cytolytic T (Tc) Cells Tc exiting the thymus are pre-Tc cells, i.e. have TCR that can recognize antigen, but are not mature and cannot kill until “armed” To become armed requires two signals: Recognition by TCR of specific antigen associated with class I MHC, and Exposure to cytokines (IL-2 and IFN-γ)

Mechanism of Arming Tc Cells Class I MHC 1. Cell expressing class I MHC presents antigen ( ) to a pre-Tc cell Pre-Tc cell 2. Pre-Tc cell differentiates to functional Tc cell Tc cell 4. Target cell is killed 3. Tc recognizes antigen on class I MHC-expressing target cell

Features of Tc Killing Antigen-specific Requires cell-cell contact Each Tc capable of killing many target cells

Main Mechanism of Tc Killing Tc granules contain perforin and granzymes Upon contact with target cell, granule contents released, perforin polymerizes and forms channel in target cell membrane Granzymes (serine proteases) enter target cell through channel, activate caspases and nucleases, lead to apoptosis of target cell

Mechanism of Tc Killing Tc cell Tc cell Perforin monomers Granzymes Perforin polymerizes Ca++ Polyperforin channels Target cell Target cell

Steps in Tc Killing Tc cell 1. Tc recognizes antigen on target cell 2. A lethal hit is delivered by the Tc using agents such as perforin or granzyme B Target cell 3. The Tc detaches from the target cell Tc cell Target cell 4. Target cell dies by apoptosis Target cell

Natural Killer (NK) Cells Derived from bone marrow Lack most markers for T and B cells (do not have TCR) Do not undergo thymic maturation Express CD56, a specific NK marker Express a receptor for Fc portion of IgG, called FcRIII (CD16) Cytokines (IL-2) promote differentiation into lymphokine-activated killer (LAK) cells

NK Cell Effector Mechanisms Mechanism of killing similar to those of Tc cells Not MHC-restricted Susceptibility of target cell to killing is inversely proportional to expression of class I MHC (killer inhibitory receptors (KIR) on NK cells recognize class I MHC and prevent killing)

NK Effector Mechanisms (continued) IgG-coated target cells recognized by FcRIII (CD16) are killed by antibody-dependent cell-mediated cytotoxicity (ADCC) Lymphokine-activated killer cells (LAK) kill broader range of cells than do NK cells