Cell-mediated Immunity

Chapter 21: Adaptive Immunity – Cellular (cell-mediated) Mechanisms

Introduction

• Lecture by Dr. Andrea Foskett, BIOL 2402, Covers pages 791-805 of the text.

Cellular Immune Response

• Primary Function: T cells defend against intracellular antigens.

• **Types of T Cells:

  • T cells directly kill infected or abnormal cells.

  • Other T cells release chemicals regulating the immune response.**

• T Cell Populations:

  • Identified by glycoprotein surface receptors displayed (CD4 or CD8):

  • CD4 Cells:

    • Usually become Helper T Cells (TH).

    • Activate B cells, other T cells, and macrophages.

    • Direct adaptive immune responses.

    • Some become Regulatory T Cells (Treg) that moderate immune response.

    • Can also become memory T cells.

  • CD8 Cells:

    • Become Cytotoxic T Cells (TC) that destroy cells harboring foreign antigens.

    • Also develop into memory T cells.

• Naive T Cells: Simply termed CD4 or CD8 cells until activated.

Major Types of T Cells and MHC Proteins

• MHC Proteins play a crucial role in T cell activation.

• T cells respond to processed fragments of antigens displayed on surfaces of cells.

  • Antigen Presentation: Critical for naive T cell activation.

  • MHC Classes:

  • Class I MHC Proteins: Found on all nucleated cells (except RBCs).

    • Present endogenous antigens (proteins synthesized in the cell).

    • Crucial for CD8 cell activation, informing TC cells about intracellular pathogens.

  • Class II MHC Proteins: Found on Antigen Presenting Cells (APCs) e.g., dendritic cells, macrophages, B cells.

    • Present exogenous antigens (that are engulfed and processed).

    • Recognized by helper T cells as a signal that assistance is required.

MHC Restriction

• Differs in Binding:

  • CD4 (TH cells): Bind only to class II MHC proteins on APC surfaces.

  • CD8 (TC cells): Bind only to class I MHC proteins on APC surfaces.

• Antigen Presentation by APCs:

  • Dendritic cells can present endogenous antigens obtained from other cells on class I MHCs.

Role of MHC Proteins in Cellular Immunity

• Class I MHC Proteins:

  • Displayed by: All nucleated cells.

  • Recognized by: Naive CD8 cells and cytotoxic T cells.

  • Message Sent:

  • Endogenous antigens: "I belong to self but have been invaded. Kill me."

• Class II MHC Proteins:

  • Displayed by: APCs (dendritic cells, macrophages, B cells).

  • Recognized by: Naive CD4 cells and helper T cells.

  • Message Sent:

  • Exogenous antigens: "I belong to self but have captured a foreign invader. Help mount a defense."

T Cell Activation

• Two-step Process:

1. Antigen Binding: T cell receptors (TCRs) bind to antigen-MHC complexes on APC surface.

2. Co-stimulation: Requires T cells to bind to other receptors on APC to receive co-stimulatory signals (e.g., from cytokines such as IL-1 and IL-2).

• Both steps are essential for clonal selection, leading to:

  • Proliferation.

  • Differentiation into effector and memory cells.

Proliferation and Differentiation of T Cells

• Once activated, T cells undergo:

  • Enlargement & Proliferation in response to cytokines.

  • Differentiation: Perform functions according to their T cell class.

• Primary T cell response peaks within one week.

  • Apoptosis occurs between days 7 and 30 as a mechanism to eliminate excess activated T cells.

  • Benefit of Apoptosis: Helps to prevent hyperplasia and cancer.

• Memory T Cells: Remain after primary response to mediate secondary responses.

Cytokines in Immune Response

• Function: Chemical messengers mediating immune responses.

• Types of cytokines include interferons and interleukins.

  • IL-1: Released by macrophages to co-stimulate bound T cells.

  • IL-2: Acts as a growth factor stimulating the division of T cells.

Roles of Helper T Cells (TH)

• Central Role: Activates both humoral (B cells) and cellular (T cells) arms of immunity.

• Upon activation by APC presentation of antigen, TH cells:

  1. Activate B and T cells.

  2. Induce proliferation of T and B cells.

• Cytokines: Released by TH cells recruit additional immune cells.

• Significance: Without TH cells, there is no effective immune response.

Activation of B Cells by Helper T Cells

• Helper T Cells Interaction: Directly interact with B cells displaying antigen fragments bound to MHC II receptors.

• Stimulation of B Cell Division: Encourages rapid division and begins antibody formation.

• T Cell-Independent Antigens: B cells may be activated without TH cells but produce a weaker and shorter-lived response.

• T Cell-Dependent Antigens: Most antigens require TH cell co-stimulation for effective B cell activation.

Activation of CD8 Cells by Helper T Cells

• Requirement for TH Cells Activation: CD8 cells require TH cells for stimulation to become cytotoxic T cells.

  • TH cells cause dendritic cells to express co-stimulatory molecules, necessary for CD8 cell activation.

Helper T Cells Amplification of Innate Defenses

• Amplify Innate Immune Response:

  • Activate macrophages making them more potent killers.

  • Mobilize additional lymphocytes and other white blood cells.

Cytotoxic T Cells (TC)

• Function: Directly attack and kill other cells including:

  • Virus-infected cells, intracellular bacteria or parasites, cancer cells, and foreign cells from transplants.

• Methods of Attack:

  • Lethal Hit 1: Release of perforins and granzymes by exocytosis.

  • Perforins create pores in target cell membranes, allowing granzymes to enter, stimulating apoptosis.

  • Method of Attack 2: TC cell binds to a specific receptor on target cell to stimulate apoptosis directly.

Regulatory T Cells (TReg)

• Function: Dampen the immune response by either:

  • Direct contact inhibition.

  • Release of inhibitory cytokines such as IL-10 and TGF-β.

• Importance: Play a crucial role in preventing autoimmune reactions by suppressing self-reactive lymphocytes occurring outside lymphoid organs.

Organ Transplants

• Types of Grafts:

  1. Autografts: From one body site to another in the same individual.

  2. Isografts: Between identical twins.

  3. Allografts: Between individuals who are not identical twins.

  4. Xenografts: From another species.

• Success Factors: Relies on similarity in tissue types, with autografts and isografts being the most successful if no infection or poor blood supply is present.

• Allograft Matching: Requires close matching of ABO and MHC antigens.

• Prevention of Rejection:

  • Immunosuppressive Therapy: Use of corticosteroids, anti-proliferative drugs, and immunosuppressants post-surgery.

Immunosuppressive Therapy Problems

• Risks of Therapy:

  • Suppresses patient's immune system, increasing vulnerability to infections (bacterial/viral) and potentially resulting in death.

• Challenge: Balancing immunosuppressive drugs for graft survival without toxicity.

• Statistics: In best circumstances, rejection occurs after approximately 10 years in 50% of patients.

Immunodeficiencies

• Types: Congenital and Acquired conditions that impair immune function.

  • Severe Combined Immunodeficiency (SCID): Genetic mutations leading to deficits in B and T cells; treated with bone marrow transplants.

  • Hodgkin’s Lymphoma: Acquired immunodeficiency caused by cancer of B cells, resulting in decreased lymph node activity.

AIDS and HIV

• HIV's Impact: Interferes with helper T cells, crippling the immune system.

• Transmission Sources: Blood, semen, vaginal secretions, via transfusions, contaminated needles, sexual intercourse, and childbirth.

• Mechanism:

  • Destroys TH cells leading to depression of cellular immunity.

  • Enters cells, using reverse transcriptase to integrate into host DNA (as a provirus) to replicate.

• Treatment Strategies:

  • Antiviral drugs and antiretroviral therapy (ART) to manage treatment and control virus replication.

Autoimmune Diseases

• Definition: Immune system fails to distinguish between self and non-self, producing autoantibodies that attack body tissues.

• Examples of Autoimmune Diseases: Multiple sclerosis, myasthenia gravis, Graves' disease, type 1 diabetes mellitus, systemic lupus erythematosus (SLE), and rheumatoid arthritis.

• Treatment Options:

  • Suppression of the immune system via anti-inflammatory drugs and blocking techniques.

  • Research includes the activation of regulatory T cells and promoting self-tolerance via vaccines.

Mechanisms of Autoimmune Diseases

• Activation of Self-Reactive Lymphocytes Can Be Triggered By:

  • Foreign antigens resembling self-antigens.

  • Antibodies reacting with both foreign and self-antigens.

  • Appearance of new self-antigens due to genetic mutations or infectious damage.

Hypersensitivities

• Definition: Immune responses against perceived harmless threats that lead to tissue damage.

• Types of Hypersensitivities:

  • Distinction based on time course and involvement of antibodies or T cells.

  • Antibody-mediated: Immediate (type I) and sub-acute (type II & III).

  • T cell-mediated: Delayed (type IV).

Immediate (Type I) Hypersensitivity

• Characteristics:

  • Begins moments after exposure to an allergen. First contact is asymptomatic, leading to sensitization.

  • Reactions can be localized or systemic.

  • IgE antibodies produced and bind to mast cells, subsequently triggering histamine release during later exposures causing allergic reactions.

• Reactions::

  • Local Reactions: In areas like skin/mucosa leading to symptoms such as runny nose or asthma.

  • Systemic Response: Anaphylactic shock resulting from widespread mast cell activation leading to severe consequences such as circulatory collapse.

• Treatment for Anaphylaxis: Administration of epinephrine.

Diagram for Allergic Response

• Mechanism Summary:

  • Antigen (allergen) stimulates plasma cells producing IgE antibodies that attach to mast cells, which upon subsequent antigen exposure release histamine, leading to allergic symptoms.