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

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

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

4. 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

5. 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

6. 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

7. 1. Antigen presentation toB7
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

8. 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

9. 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

10. 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

11. 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)

12. 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

13. 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

14. 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

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

16. 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)

17. 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

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

19. 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

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

21. 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

22. 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

23. 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)

24. 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