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

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

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

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

Activation of T Cells

• Antigen recognition– MHC-TCR

• Activation– Cytokines

• Clonal expansion

• Differentiation– CD4+, CD8+

• Effector function

Adapted from Abbas & Lichtman’s Basic Immunology 5-2

Peripheral

Cytokines

Cytokines

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

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

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

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

CD8+ T Cell Activation

Adapted from Abbas & Lichtman’s Basic Immunology 5-7

• 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

Effector Function of CD4+ T Cells

• Activation of macrophages.– Expression of CD40L by CD4+ T cells.

– CD40L bind to CD40 on Macrophages.

– Secretion of cytokines (IFN) by CD4+ T cells.

– Results in macrophage killing of phagocytosed microbe.

Abbas & Lichtman’s Basic Immunology 5-10B

•Differentiated effector cells appear 3-4 days after exposure to microbe.

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

Function of Th1 CD4+ T Cells

• 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

IL-12

Function of Th1 CD4+ T Cells

• Th1 cells secrete IFN– 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.

Adapted from Abbas & Lichtman’s Basic Immunology 5-11A

IL-12

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

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

• 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

Effector Function of CD8+ Cytotoxic T Lymphocytes

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

Resistance to Cell-Mediated Immunity

• Inhibition of phagolysosome fusion.• Mycobacteria escapes death by avoiding enzymes in

lysosome.

Abbas & Lichtman’s Basic Immunology 6-12

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

• Production of inhibitory cytokines– EBV secretes IL-10 (similar to IL-4) that inhibits

macrophage activation.

Abbas & Lichtman’s Basic Immunology 6-12

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

Resistance to Cell-Mediated Immunity

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

Objectives

1. Describe T cell maturation and be able to differentiate naïve and effector T cells.

2. Describe the process of T cell activation

3. Describe the development and functions of Th1 and Th2 cells.

4. Describe the mechanism of T cell cytotoxicity.