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

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 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

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

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

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

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

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 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

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

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

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

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

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

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

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 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.