1. Lecture #10
Aims
Describe T cell maturation and be able to differentiate naïve and effector T cells.
Differentiate the development and functions of Th1 and Th2 cells.
Describe the mechanism of T cell cytotoxicity.
Readings: Abbas & Lichtman, Chapters 4, 5 & 6

2. T Cell Maturation and Selection
Occurs in the thymus.
Positive selection
T cells must recognize a MHC molecule in order to survive.
Makes sure TCR molecule can recognize MHC + peptide.
Failure of positive selection
No recognition of MHC+ peptide.
Negative selection
T cells who strongly recognize a MHC molecule undergo apoptosis.
Eliminates self protein reacting T cells.
Adapted from Abbas & Lichtman’s Basic Immunology 4-13

3. Intracellular Microbes
Cell mediated immunity is responsible for intracellular microbial infections.
Common intracellular infections
Phagocytosed microbe that survive in phagolysosomes.
Microbe that escapes into cytoplasm.
Abbas & Lichtman’s Basic Immunology 5-1A

4. Intracellular Microbes
Microbes that bind to membrane receptors and enter a cell’s cytoplasm in order to infect a cell.
Abbas & Lichtman’s Basic Immunology 5-1B

5. Activation of T Cells Antigen recognition Activation Clonal expansion
MHC-TCR
Activation
Cytokines
Clonal expansion
Differentiation
CD4+, CD8+
Effector function
Cytokines
Cytokines
Peripheral
Adapted from Abbas & Lichtman’s Basic Immunology 5-2

6. MHC-TCR Interaction
TCR recognizes antigen (peptide) within MHC molecules.
CD4 binds to MHC class II molecules (CD8 to class I).
Signaling begins with phosphorylation of the ζζ associated with _CD3_.
Abbas & Lichtman’s Basic Immunology 5-4

7. CD4+ T Cell Activation Activation requires two signals.
1) MHC/peptide antigen binding to TCR.
2) Costimulatory molecule on APC binding to specific receptors on T cell.
B7-1 (CD80) or B7-2 (CD86) on APC binding to CD28 on T cell.
Adapted from Abbas & Lichtman’s Basic Immunology 5-6

8. CD4+ T Cell Activation
Activated T cells produce cytokines and cytokine receptors.
IL-2
High affinity IL-2 receptor.
Resulting in clonal proliferation and differentiation of that T cell.
Adapted from Abbas & Lichtman’s Basic Immunology 5-6

9. Lecture #10
CD4+ T Cell Activation
If no costimulation occurs when TCR binds to MHC / Peptide, T cell becomes nonresponsive (anergy) or undergo apoptosis.
Only activated APCs express costimulatory molecules.
Thus only naïve T cells in direct contact with APC containing microbial antigen will be activated.
Adapted from Abbas & Lichtman’s Basic Immunology 5-6

10. CD8+ T Cell Activation
Antigen presentation by APC via MHC class I (infected APC).
APC express costimulator molecules.
Phagocytosed infected cell by APC results in antigen presentation via MHC class II to CD4+ T cell and MHC class I to CD8+ T cell.
CD4+ T cells secrete cytokines to activate CD8+ T cells.
10,000 fold
Adapted from Abbas & Lichtman’s Basic Immunology 5-7

11. Effector Function of CD4+ T Cells
Differentiated effector cells appear 3-4 days after exposure to microbe.
Activation of macrophages.
Expression of CD40L by CD4+ T cells.
CD40L bind to CD40 on Macrophages.
Secretion of cytokines (IFNg) by CD4+ T cells.
Results in macrophage killing of phagocytosed microbe.
Abbas & Lichtman’s Basic Immunology 5-10B

13. Effector Function of CD4+ T Cells
Activation of a B cell.
Expression of CD40L by CD4+ T cells.
CD40L bind to CD40 on B cells.
Secretion of cytokines (IL-4) by CD4+ T cells.
Results in B cell secretion of antibody.
Abbas & Lichtman’s Basic Immunology 5-10B

14. Function of Th1 CD4+ T Cells
IL-12
Macrophages and dendritic cells respond to bacterial or viral infections by secreting _IL-12_ which causes naïve CD4+ T cells to differentiate into Th1 cells.
Adapted from Abbas & Lichtman’s Basic Immunology 5-11A

15. Function of Th1 CD4+ T Cells
Th1 cells secrete IFNg.
Macrophage activation.
Stimulates expression of MHC class II.
Stimulates the expression of B7 costimulators.
B cell production of IgG subclasses involved in phagocytosis via Fc receptors.
IL-12
Adapted from Abbas & Lichtman’s Basic Immunology 5-11A

16. Function of Th2 CD4+ T Cells
If there is no production of IL-12 by the APC then the T cell itself secretes IL-4 inducing its differentiation into the Th2 phenotype.
This is what happens in infections by helminths which are too big to be phagocytosed.
Abbas & Lichtman’s Basic Immunology 5-11B

17. Function of Th2 CD4+ T Cells
Th2 cells secrete IL-4
Stimulates the production of (class switch to) IgE by B cells.
Th2 cells secrete IL-5
Activates eosinophils.
Th2 cytokines (IL-4) inhibit macrophage activation and Th1 mediated immunity.
Abbas & Lichtman’s Basic Immunology 5-11B

18. Effector Function of CD8+ Cytotoxic T Lymphocytes
CD8+ cytotoxic T lymphocytes recognize MHC class I with peptides on infected cells.
Differentiated cytotoxic T lymphocytes do not require costimulation or T cell help for activation.
Abbas & Lichtman’s Basic Immunology 6-10

19. Effector Function of CD8+ Cytotoxic T Lymphocytes
Cytotoxic T lymphocytes kill target cells by releasing granule contents.
Perforin polymerizes resulting in pores in target cell membranes.
Granzymes enter target cell through perforin pores and activate caspases resulting in apoptosis.
Abbas & Lichtman’s Basic Immunology 6-10

20. Resistance to Cell-Mediated Immunity
Inhibition of phagolysosome fusion.
Mycobacteria escapes death by avoiding enzymes in lysosome.
Abbas & Lichtman’s Basic Immunology 6-12

22. Resistance to Cell-Mediated Immunity
Inhibition of class I MHC expression.
CMV & EBV Inhibit proteosomal activity.
HSV Inhibits transport of peptides into ER.
CMV Removes class I MHC from ER.
Abbas & Lichtman’s Basic Immunology 6-12

23. Resistance to Cell-Mediated Immunity
Production of inhibitory cytokines
EBV secretes IL-10 (similar to IL-4) that inhibits macrophage activation.
Abbas & Lichtman’s Basic Immunology 6-12

24. Resistance to Cell-Mediated Immunity
Production of soluble cytokine receptors.
Quench cytokines resulting in lack of cytokine activity.
Pox virus secretes soluble IL-1 and TNF receptors.
Abbas & Lichtman’s Basic Immunology 6-12

25. Next Time Describe the humoral immune response.
Compare and contrast the primary and secondary antibody responses.
Compare and contrast T-dependent and T-independent antigens and the antibody response to each.
Describe effector functions of antibodies including neutralization and ADCC.
Readings: Abbas & Lichtman, Chapters 7 & 8

26. Objectives
Describe T cell maturation and be able to differentiate naïve and effector T cells.
Describe the process of T cell activation
Describe the development and functions of Th1 and Th2 cells.
Describe the mechanism of T cell cytotoxicity.