Lesson 6.3

Learning Objectives

• Recognize the functions of different T cell subsets.

• Comprehend the importance of T cells in immune regulation and defense.

Effector T Cells – General Properties

1. Movement from Lymphoid Tissue

   • Armed effector T cells leave the lymphoid tissue.

   • They migrate to sites of injury or infection via the bloodstream.

2. Migration Mechanism

   • T cells migrate to the tissues through activated endothelium.

3. Scanning for Ligands

   • T cells scan tissues for MHC (Major Histocompatibility Complex): antigenic peptide ligands.

4. Antigen Recognition

   • Recognition of the antigen triggers effector function.

   • This process does not require co-stimulation.

5. Effects of TCR (T Cell Receptor) Interaction

   • The interaction of TCR with antigenic ligands has two main effects:
     i. Cytoskeleton reorganizes to focus effector molecules onto the target cell.
     ii. Triggers the release of effector molecules.

6. Effector Mechanisms

   • Effector mechanisms are mediated by both cell surface and soluble molecules.

CD4+ T Cell Differentiation

1. Role of Cytokines

   • Cytokines produced by Antigen-Presenting Cells (APCs) determine CD4+ T cell differentiation.

2. Impact on Immune Response

   • This differentiation influences whether cell-mediated or humoral responses dominate.

3. Cytokine Associations

   • IL-6 burst is associated with the development of T Follicular Helper (TFH) cells.

   • IL-12 and IFN-g are associated with the differentiation into TH1 cells.

   • IL-4 is associated with differentiation into TH2 cells.

TH1 Cell Function

1. Mechanism of Action

   • TH1 cells produce bound TNF-a, which interacts with TNF-a receptors on macrophages.

2. Activation of Macrophages

   • Activates the anti-microbial properties of macrophages through:
     i. Increased efficiency of lysosome-phagosome fusion.
     ii. Stimulation of the synthesis of Reactive Oxygen Species (ROS), Nitric Oxide Synthase (NOS), and defensins.
     iii. Stimulation of MHC class II and TNF-a receptor expression.

3. Antibody Production

   • Stimulates the production of specific antibodies (IgG1 & IgG3) that mediate pathogen destruction by phagocytes.

TH1 Cell Details

1. Recognition Process

   • Upon recognition of MHC Class II:antigenic peptide, cytokines and cell surface effector molecules are synthesized.

2. Key Cytokines Produced

   • IFN-g: Activates macrophages.

   • TNF-a: Acts synergistically with IFN-g; activates endothelium.

   • LT-b (Lymphotoxin beta): Kills chronically infected macrophages.

   • CD40L: With IFN-g, activates macrophages.

TH2 Cell Function

1. Response Type

   • TH2 cells mediate an anti-parasitic response.

2. Migration Pattern

   • These cells migrate to epithelial sites.

3. Cytokines Produced

   • Produce IL-4, IL-13, IL-5, IL-9, and IL-10.

4. Effects on Other Cells

   • Recruit, activate, and promote the survival of basophils, eosinophils, and mast cells.

5. Macrophage Activation

   • Activate macrophages into alternatively activated macrophages.

6. Impact on Epithelial Tissue

   • IL-4/IL-13 affect the epithelium by:

     • Increasing mucous production and flow.

     • Reducing the attachment of parasites.

TH2 Cell Additional Functions

1. Survival Factors

   • IL-5 and IL-9 promote the survival of eosinophils, mast cells, and basophils.

2. Anti-inflammatory Role

   • IL-10 is anti-inflammatory and protects commensal bacteria in the gut.

3. Immunoglobulin Production

   • IL-4 mediates IgE production.

   • IL-5 combined with TGFb stimulates IgA production.

T Follicular Helper (TFH) Cell Function

1. B Cell Activation

   • TFH cells mediate B cell activation.

   • They remain in lymphatic tissue and migrate to the edges of B cell follicles.

2. B Cell Interaction

   • B cells encounter antigens in follicles and migrate to the edge of the T cell area.

3. Antigen Processing

   • B cells internalize, process, and present antigen:MHC Class II to TFH cells.

4. Rescue of B Cells

   • Binding to a TFH cell rescues a B cell from apoptosis.

5. CD40L Interaction

   • TFH cells express CD40L, which binds to CD40 on B cells.

TFH Cell Mechanisms

1. Proliferation and Differentiation

   • CD40L:CD40 interaction stimulates proliferation and differentiation into plasma cells in the germinal center.

2. Germinal Center Formation

   • Activated B cells move to follicles and proliferate to form a germinal center.

3. Affinity Maturation and Isotype Switching

   • In the germinal center, activated B cells undergo affinity maturation and class switching.

   • These processes are mediated by follicular dendritic cells (FDCs) and TFH cells.

TFH Cell Process Insights

1. Mechanism of Antigen Presentation

   • The process is not fully understood but involves FDCs presenting antigen to B cells, rescuing those with high affinity surface antibodies.

2. Cytokine Role in Class Switching

   • Cytokines mediate class switching during the activation of B cells.

3. Isotype Diversity

   • Isotype switching enables B cells to secrete various antibody isotypes (IgG, IgA, IgE).

4. Affinity Maturation Effects

   • Affinity maturation generates high-affinity antibodies through somatic hypermutation of V region genes.

5. B Cell Maturation

   • Activated B cells can mature into:

   1. Plasma cells, which secrete antibodies.

   2. Memory cells, which retain immunological memory.

Cytotoxic T Cell (Tc) Function

1. Secretory Granules Composition

   • Preformed secretory granules in Tc cells contain perforins and granzymes.

2. Mechanism of Action

   • Upon binding to a ligand, secretory granules are released.

3. Perforin Function

   • Perforins polymerize to form membrane pores approximately 160 Å in diameter.

4. Granzyme Activation

   • Granzymes enter the cell and activate apoptosis.

5. Death Induction Mechanisms

   • Target cell death can also occur via interactions with cell surface molecules.

6. Prevention of Infection Spread

   • Apoptotic cell death prevents the spread of infectious agents.

Tc Cell - Cytokines Released

1. Cytokine Functions

   • Tc cells release multiple cytokines such as:

     • IFN-g: Inhibits viral replication, increases the expression of MHC class I, and enhances the transcription of genes TAP-1 and TAP-2; also activates macrophages.

     • TNF-a: Works synergistically with IFN-g for macrophage activation.

     • TNF-b: Works in conjunction with IFN-g to induce target cell death.

Other T Cell Populations

1. Memory T Cells

   • Persist after an immune response has resolved.

2. Regulatory T Cells (TREG)

   • Suppress immune responses in an antigen-specific manner.

3. Subpopulation Characteristics

   • No distinct subpopulation has been identified for regulatory T cells.

4. Development Pathways

   • Develop from CD4+ cells in the periphery or during T cell development in the thymus.

5. Roles of TREGs

   • Suppress responses to autoantigens and limit responses to high levels of antigen, thereby minimizing tissue destruction from chronic immune cell activation and effector molecule release.

Summary of T Cell Functions

1. Overview of T Cell Roles

   • Different types of T cells have specific roles in regulating the immune system and defending against pathogens.

2. Th1 Cells

   • Activate macrophages and cytotoxic T cells to combat intracellular pathogens.

3. Th2 Cells

   • Enhance antibody production by activating B cells, effective against extracellular parasites.

4. T Follicular Helper Cells (TFH)

   • Assist B cell activation and antibody production, crucial for memory B cell formation.

5. CD8+ Cytotoxic T Cells

   • Identify and eliminate infected or cancerous cells via cytotoxic mechanisms.

6. Regulatory T Cells (Tregs)

   • Prevent excessive immune responses and autoimmune reactions, maintaining immune homeostasis.

7. Memory T Cells

   • Enable rapid response to previously encountered pathogens, providing long-term immunity.