lecture 3.3

Adaptive Immunity

General Overview

  • Instructor: Tim Maley, PhD (University of Arizona)

  • Course: PSIO 202

  • Email: maleytim@arizona.edu

  • Office: Gittings 113

Learning Objectives (Saladin, Ch. 21)

  • Comparison of Immune Systems:

    • Compare and contrast the general features of innate and adaptive immunity.

  • Identifying Foreign Proteins:

    • Identify how proteins from other organisms can be distinguished from human proteins.

  • Information Sources:

    • Determine sources providing information about proteins from invading organisms (bacterial or viral).

  • MHC Proteins:

    • Define MHC proteins and their role in sharing protein sequence information.

  • MHC Function Comparison:

    • Compare and contrast MHC Class I and Class II functions.

  • Non-Self Antigen Recognition:

    • Identify the receptor protein that enables the immune system to recognize non-self antigens.

  • T Cell Training:

    • Explain how T cells are trained to identify only non-self antigens.

  • Cell Surface Receptors in Immune Response:

    • Describe the four major cell surface receptors involved in immune responses.

Immune System Functions

  • T Cells:

    • Specifically attack and destroy disease agents.

  • B Cells:

    • Utilize antibodies to tag disease agents for removal.

Antigens

  • Definition:

    • Substances that provoke an immune response.

  • Complete Antigen:

    • Immunogenic: Stimulates specific lymphocytes to multiply.

    • Reactive: Reacts with activated lymphocytes and antibodies.

    • Includes larger molecules such as foreign proteins, polysaccharides, lipids, and nucleic acids.

  • Incomplete Antigen (Hapten):

    • Often not immunogenic, but reactive.

    • Combines with parts of the immune system to evoke a reactivity.

    • Typically smaller molecules including peptides, nucleic acids, and hormones.

Antigen Structure

  • Antigen-Binding Sites of Antibodies:

    • Identified as Antibody A, B, C which bind to antigenic determinants (also known as epitopes).

Antigens & MHC Proteins

  • Self vs. Non-Self Recognition:

    • Major Histocompatibility Complex (MHC):

    • Also referred to as Human Leukocyte Antigen (HLA) complex.

    • Comprised of over 200 genes located on chromosome 6.

    • Exhibits incredible variation at MHC loci among individuals.

    • MHC proteins function to hold antigens for presentation to lymphocytes, aiding self vs. non-self determination.

Antigen Presentation via MHC-I Proteins

  • General Function:

    • All nucleated cells (including infected cells) present endogenous (self) antigens associated with MHC-I molecules.

  • Cytotoxic T Cells:

    • T cell receptors (TCRs) interact with MHC-I presented self-antigens to help distinguish self from non-self.

Protein Random Sampling Approach

  • Mechanism:

    • Nucleated cells perform random sampling of cytoplasmic proteins by:

    • Digesting proteins into peptide fragments 8-15 amino acids long.

    • Displaying those fragments on MHC-I molecules.

    • This allows representation of cellular protein production and protection against infections that utilize cellular machinery (e.g., viral infections).

    • Peptide fragments of at least 8 amino acids can differentiate human from bacterial protein sequences.

Antigen Presentation via MHC-II Proteins

  • Mechanism:

    • Specialized immune cells, termed antigen-presenting cells (APCs), present exogenous (non-self) antigens with MHC-II molecules.

  • Cell Types Involved:

    • Engulf non-self antigens primarily macrophages, dendritic cells, and B lymphocytes, subsequently presenting fragments through MHC-II to T lymphocytes.

Importance of Antigen Presentation

  • Universal Requirement:

    • All nucleated cells must present self-antigens through MHC-I.

    • Cells failing to present self-antigens are marked for death by Natural Killer (NK) cells.

  • Context:

    • Prevents intracellular pathogens from hiding within host cells.

    • MHC-I presented self-antigens are inspected by T cells through their TCR.

Role of MHC Proteins in Cellular Immunity (Table 20.6)

  • Class I MHC Proteins:

    • Displayed by all nucleated cells.

    • Recognized by naive CD8 cells (cytotoxic T cells) using CD8 protein.

    • Deals with endogenous antigens (e.g., intracellular pathogens or proteins produced by cancer cells).

    • Messages:

    • If an APC: "I belong to self, but have captured a foreign invader. This is what it looks like. Kill any cell that displays it."

    • If not an APC: "I belong to self, but have been invaded or become cancerous. Kill me!"

  • Class II MHC Proteins:

    • Presented by antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B cells.

    • Recognized by naive CD4 cells (helper T cells) via CD4 protein.

    • Deals with exogenous antigens (e.g., phagocytized extracellular pathogens).

    • Messages:

    • "I belong to self, but have captured a foreign invader. This is what it looks like. Help me mount a defense against it."

Innate Defenses: Cells of the Immune System

  • Definition:

    • Immunocytes include circulating leukocytes, tissue macrophages, and dendritic cells.

  • Categories of Immune Cells:

    • Basophils

    • Neutrophils (50-70% of WBCs, also called "polys" or "segs.")

    • Eosinophils (1-3% of WBCs)

    • Mast Cells

    • Monocytes

    • Lymphocytes (20-35% of WBCs, includes B lymphocytes, T lymphocytes, and their derivatives)

    • Functionality:

    • Release chemicals that mediate inflammation and allergic responses (e.g., Basophils).

    • Ingest and destroy invaders (e.g., Neutrophils, Monocytes, Dendritic Cells).

    • Recognize pathogens and activate other immune cells by antigen presentation.

Adaptive Defenses

  • Lymphocytes Overview:

    • B Lymphocytes:

    • Key for humoral immunity; effector cells include plasma cells (secrete antibodies) and memory cells (long-lived, key for second response).

    • T Lymphocytes:

    • Key for cellular immune response; effector cells comprise helper T cells (assist other cells in mounting responses) and cytotoxic T cells (attack and destroy invaders), plus regulatory T cells (moderate immune response).

  • Memory Cells:

    • Both B and T lymphocytes have memory cells that are long-lived and crucial for rapid responses in subsequent exposures to antigens.

Lymphopoiesis

  • Lymphocyte Development Pathway:

    • Humoral Immunity: B cells developed from T stem cells in the red bone marrow.

    • Cellular Immunity: T cells mature in the thymus before entering the circulation.

  • Illustration of Lymphopoiesis:

    • T stem cells -> Immunocompetent T cells -> Plasma cells in lymph nodes, spleen, tonsils, and other lymphatic tissues.

T Lymphocyte Maturation

  • Site:

    • Occurs in primary lymphatic organs, specifically the thymus.

  • Selection Process:

    • T cells must show:

    • Immunocompetence: Ability to recognize MHC proteins.

    • Self-tolerance: Unresponsiveness to self-antigens.

    • Approximately 2% of T cells succeed in selection to enter circulation.

Thymic Structure and Function

  • Outer Cortex:

    • Immature T cells separated from blood to prevent premature activation.

    • Blood-thymus barrier.

    • Testing for immunocompetence (Positive Selection):

    • Ability to recognize and bind to MHC proteins.

    • Failure results in reshuffling DNA for antigen receptor and retrying (Second failure leads to death).

  • Inner Medulla:

    • Like “grad school” for T cells.

    • Exposure to blood and APCs.

    • Testing for self-tolerance (Negative Selection):

    • Unresponsiveness to self-antigens.

    • Failure results in death or inactivation (anergy).

B Lymphocyte Maturation

  • Location:

    • Occurs entirely within red bone marrow.

  • Selection Rate:

    • Only 10% pass both positive and negative selection processes.

  • Post-maturation Pathway:

    • B cells move to circulation to populate secondary lymphatic organs in search of their corresponding antigen.