Adaptive Immunity: Antigens, T-Cell Lineages, and MHC Presentation

Core Concepts of Antigenicity and Immunogenicity

• Definition of Antigen: An antigen refers to anything that can activate an immune response.
• Immunogenicity: This is the capacity of a substance (trigger) to activate the immune response.
• Antigenic Structures: Antigens can be composed of various molecules, including:
      * Proteins (e.g., viral spike proteins).
      * Polysaccharides (e.g., bacterial capsules).
      * Lipids.
      * Small molecules.
• Haptens (Incomplete Antigens): These are small molecules that cannot trigger an immune response on their own. They must attach to a larger carrier, such as a protein or polysaccharide, to become immunogenic.
      * Example: Penicillin can act as a hapten in some individuals.
• Determinants of Immunogenicity: The ability of a molecule to act as an antigen is not "set in stone"; it is influenced by:
      * Size.
      * Molecular complexity.
      * Chemical composition.

Epitopes and Receptor Specificity

• Epitopes: These are the specific regions or structures on the surface of an antigen that immune receptors actually recognize and bind to. While a whole pathogen is called an antigen, it contains multiple different epitopes.
• Lymphocyte Receptors:
      * T Cell Receptors (TCR): Located on the surface of T cells.
      * B Cell Receptors (BCR): Located on the surface of B cells. They are Y-shaped and have two antigen-binding sites.
• Receptor Homogeneity: On a single T or B cell, there are thousands of receptors, but every single receptor on that specific cell is identical and recognizes the exact same epitope.
      * Specificity Analogy: If an epitope is shaped like a triangle, it can only bind to a "triangle receptor." It cannot bind to a spherical receptor. This specificity is why adaptive immunity provides a targeted response.
• Population Diversity: Although an individual cell is restricted to one epitope, the body possesses a vast number of different T and B cells, each with different receptors, allowing the immune system to recognize millions of different antigens.

B Cell and T Cell Differentiation

• Naïve Cells: These cells are mature but have not yet encountered their specific antigen. They reside in lymphoid tissues waiting for antigen presentation.
• Activation: Occurs when a naïve cell binds to its matching epitope and receives chemical signals called cytokines.
• Clonal Expansion (Proliferation): The activated cell divides repeatedly to increase its population. These "clones" are genetically identical and possess the exact same receptor as the original activated cell.
• Effector Cells: Specialized cells that actively fight the current infection.
      * Plasma Cells: The effector cells of B cells. They lose their surface receptors to become protein factories that secrete antibodies.
• Antibodies: These are secreted versions of the BCR.
      * Difference between BCR and Antibody: The BCR has a hydrophobic tail to anchor it into the phospholipid bilayer of the cell membrane. The antibody has a hydrophilic tail, allowing it to "swim" through bodily fluids to find antigens.

Functional Categories of T Cells

• T Cytotoxic Cells ($T_C$ or CTLs):
      * Full Name: Cytotoxic T Lymphocytes.
      * Role: They directly destroy infected cells (e.g., virus-infected), cancerous cells, or damaged cells.
      * Marker: They express the CD8 protein ($CD8^+$).
      * Mnemonic: The number 8 contains circles/curves that look like the letter "C" for Cytotoxic.
• T Helper Cells ($T_H$):
      * Role: Known as the "Generals" of the immune system. They do not directly attack pathogens. Instead, they coordinate the adaptive and innate responses by releasing cytokines to recruit other leukocytes.
      * Marker: They express the CD4 protein ($CD4^+$).
      * Mnemonic: "Call (C) Four (D4) Help."
• Subclasses of T Helper Cells:
      * $T_H1$: Stimulate T Cytotoxic cells ($CD8^+$).
      * $T_H2$: Stimulate B cells and assist in their activation.
      * T Regulatory ($T_{reg}$): Control and dampen the immune response once a threat is eliminated. They regulate dendritic cells, mast cells, B cells, and other T cells.

Self-Tolerance and Maturation

• Gene Shuffling: T and B cells use gene shuffling to create a massive variety of receptors. However, this process can accidentally create receptors that attack the body's own tissues.
• Screening (Self-Tolerance Training):
      * T Cells: Screened in the Thymus. They undergo Positive Selection (must recognize self-MHC) and Negative Selection (must not bind too tightly to self-antigens).
      * B Cells: Screened in the Bone Marrow. They are checked to ensure their antibodies do not bind to self-antigens. Those that fail undergo apoptosis (programmed cell death).

Major Histocompatibility Complex (MHC)

• Function: MHC proteins act as a "uniform" for cells, allowing them to present antigens to T cells. They are also known as Human Leukocyte Antigens (HLAs).
• Classes of MHC:
      * MHC I: Found on all nucleated cells in the body (not on red blood cells/erythrocytes). They present intracellular antigens (e.g., viral proteins, cancer proteins) to $T_C$ cells ($CD8^+$).
      * MHC II: Found only on Professional Antigen Presenting Cells (APCs): Macrophages, B cells, and Dendritic cells. They present extracellular antigens (e.g., bacteria, fungi) to $T_H$ cells ($CD4^+$).
• Mnemonic for MHC-T Cell Matching: MHC II has two lines, matching the two lines in the letter "H" for Helper cells.
• Clinical Relevance: MHC compatibility is the primary factor in organ transplant matching. If MHCs do not match, T cells will attack the organ, a process called allorecognition (transplant rejection).

The Four Stages of T Cell Adaptive Immunity

Stage 1: Antigen Presentation

• Intracellular Pathway (MHC I):
      1. Proteasomes (enzymes) chop intracellular viral or abnormal proteins into short fragments called peptides.
      2. Peptides enter the Endoplasmic Reticulum (ER).
      3. MHC I (located on the ER surface) binds the peptide.
      4. A vesicle transports the MHC I-antigen complex to the cell surface for inspection by $CD8^+$ T cells.
• Extracellular Pathway (MHC II):
      1. APCs engulf extracellular pathogens via endocytosis/phagocytosis.
      2. The pathogen is chopped into peptides within a phagolysosome (using lysozymes).
      3. MHC II travels from the ER in a vesicle and fuses with the phagolysosome to bind the peptide.
      4. The MHC II-antigen complex is brought to the surface for inspection by $CD4^+$ T cells.

Stage 2: Lymphocyte Activation

• Location: Secondary lymphoid tissues.
• Primary Signal: The TCR binds to the specific antigen presented on the MHC.
      * For $T_H$, CD4 binds directly to MHC II.
      * For $T_C$, CD8 binds directly to MHC I.
• Secondary Signal (Co-stimulation): Required for full activation.
      * CD28 on the T cell interacts with B7 on the APC.
• Superantigens: These are potent toxins (e.g., from certain viruses or bacteria) that force a TCR and MHC II to bind regardless of specificity. This causes a continuous, uncontrolled release of cytokines, leading to dangerous levels of inflammation.

Stage 3: Proliferation and Differentiation

• The T cell undergoes clonal expansion.
• Cytokines determine the specific subclass the cell will become:
      * $T_H1$ signals: Interleukin-12 and Interferon-gamma.
      * $T_H2$ signals: Interleukin-2 and Interleukin-4.

Stage 4: Antigen Elimination and Memory

• Effector cells perform their duties (cytolysis or cytokine coordination) to clear the pathogen, while memory cells are produced to provide long-term immunity.

Questions & Discussion

• Question (Instructor): Are the naive B cell and T cell mature or immature?
• Response (Student): Mature. They must be mature to be in lymphoid tissues and encounter antigens.
• Question (Instructor): Those chemical signals which are what?
• Response (Student): Cytokines.
• Question (Instructor): In the proliferation, it is also called clonal expansion… what is specific about clones?
• Response (Student): They are the exact same thing; they are genetically identical.
• Question (Instructor): The effector cells of the B cells was called what?
• Response (Student): Plasma cells.
• Question (Instructor): The plasma membrane is made out of what?
• Response (Student): Phospholipid bilayer.
• Question (Instructor): When do you think that they [self-reactive cells] will get eliminated? [During antigen presentation?]
• Response (Instructor): It's going to be before that, during maturation in the thymus/bone marrow.
• Question (Instructor): Why do you think that the line of the transplant list is too long?
• Response (Class): Because you have to have the closest compatibility between your MHC and the transplant.
• Question (Instructor): The short segments of the proteins are called what?
• Response (Class): Peptide.
• Question (Instructor): For T cells, what kind of cytokine will be released [for activation]?
• Response (Student): Interleukin-2.