Practice 5 structured short- and long-answer medical questions on Weekly Year 2: Cellular Immunology Exam - May 1, 2026 (Sections B & C). Review model answer...
Answer: Dendritic cells (DCs) are professional antigen-presenting cells (APCs) crucial for initiating adaptive immunity. Their primary roles include: 1. Antigen Capture and Processing: DCs efficiently capture antigens in peripheral tissues through various mechanisms (e.g., phagocytosis, macropinocytosis, receptor-mediated endocytosis). They then process these antigens into peptides. 2. Migration to Secondary Lymphoid Organs: Upon antigen uptake and activation (e.g., by PRR signaling), DCs mature and migrate from peripheral sites to draining lymph nodes or other secondary lymphoid organs. 3. Antigen Presentation: In the lymph nodes, mature DCs present processed peptide antigens to naive T cells. Exogenous antigens are presented on MHC class II molecules to CD4+ T cells, while endogenous or cross-presented antigens are presented on MHC class I molecules to CD8+ T cells. 4. Co-stimulation: DCs provide essential co-stimulatory signals (e.g., via B7.1/B7.2 binding to CD28 on T cells) required for full activation and differentiation of naive T cells, preventing anergy. 5. Cytokine Production: DCs secrete various cytokines that help shape the differentiation of activated T cells into specific effector subsets (e.g., Th1, Th2, Th17).
Answer: The 'two-signal hypothesis' states that full activation of a naive T lymphocyte requires two distinct signals from an antigen-presenting cell (APC) to prevent anergy or inappropriate immune responses. 1. **Signal 1 (Antigen-Specific Signal):** This signal is delivered when the T cell receptor (TCR) on the T cell recognizes and binds specifically to its cognate peptide antigen presented within a Major Histocompatibility Complex (MHC) molecule on the surface of an APC (e.g., a dendritic cell). For CD4+ T cells, this is MHC class II; for CD8+ T cells, it is MHC class I. This interaction provides antigen specificity. 2. **Signal 2 (Co-stimulatory Signal):** This is an antigen-independent signal provided by co-stimulatory molecules on the APC that bind to corresponding receptors on the T cell. The most critical co-stimulatory interaction involves the binding of CD28 on the T cell to B7 molecules (CD80/CD86) on the APC. This signal confirms to the T cell that the APC has encountered a pathogen and is appropriately activated. If a naive T cell receives Signal 1 in the absence of Signal 2, it typically becomes anergic (unresponsive) or undergoes apoptosis, a crucial mechanism for maintaining peripheral tolerance and preventing autoimmunity. Both signals are required for T cell proliferation, differentiation into effector cells, and cytokine production.
Answer: Immunoglobulin G (IgG) is the most abundant antibody isotype in serum and plays a critical role in various aspects of host defense: 1. **Neutralization:** IgG antibodies can bind to bacterial toxins, viruses, and microbial components, preventing them from interacting with host cells and causing damage or infection. This is a crucial mechanism for preventing disease. 2. **Opsonization:** IgG acts as an opsonin, coating pathogens (e.g., bacteria) and enhancing their uptake and destruction by phagocytic cells (macrophages, neutrophils) that express Fc receptors (FcγR) for the Fc region of IgG. 3. **Complement Activation:** IgG (specifically IgG1, IgG2, and IgG3 subclasses) can activate the classical pathway of the complement system when bound to antigens on a pathogen's surface. This leads to the formation of the membrane attack complex (MAC), promoting lysis of the pathogen, and also contributes to opsonization and inflammation. 4. **Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC):** IgG antibodies can bind to target cells (e.g., virally infected cells or tumor cells) and serve as a bridge for natural killer (NK) cells. NK cells recognize the Fc region of IgG via their FcγRIII (CD16) receptors and are then triggered to release cytotoxic granules, leading to the apoptosis of the target cell. 5. **Placental Transfer:** IgG is the only antibody isotype that can be actively transported across the placenta from mother to fetus, providing passive immunity to the newborn during the critical first months of life.
Answer: T lymphocyte tolerance is crucial for preventing autoimmunity by eliminating or inactivating self-reactive T cells. It occurs via two main mechanisms: **Central Tolerance:** * **Location:** Primarily occurs in the primary lymphoid organ, the thymus, during T cell development (thymic education). * **Mechanism:** Involves **negative selection**, where immature T cells (thymocytes) that strongly recognize self-peptide/MHC complexes with high affinity undergo apoptosis (clonal deletion). A key protein, AIRE (Autoimmune Regulator), expressed by medullary thymic epithelial cells, broadens the range of self-antigens presented in the thymus to include tissue-specific antigens, ensuring deletion of T cells reactive to these antigens. * **Outcome:** Eliminates the vast majority of highly self-reactive T cells before they mature and exit the thymus. **Peripheral Tolerance:** * **Location:** Occurs in secondary lymphoid organs (e.g., lymph nodes, spleen) and peripheral tissues, dealing with mature T cells that have escaped central tolerance. * **Mechanism:** Employs several strategies: * **Anergy:** Self-reactive T cells that encounter self-antigens presented by APCs without adequate co-stimulatory signals (Signal 2) become functionally inactivated and unable to respond to subsequent antigen exposure. * **Suppression by Regulatory T cells (Tregs):** Tregs (CD4+CD25+FoxP3+) actively suppress the activation and proliferation of self-reactive T cells through various mechanisms, including direct cell-to-cell contact and secretion of inhibitory cytokines (e.g., IL-10, TGF-β). * **Activation-Induced Cell Death (AICD):** Repeated or prolonged stimulation of self-reactive T cells by self-antigens can lead to their apoptosis, often mediated by the Fas/FasL pathway. * **Outcome:** Inactivates or eliminates self-reactive T cells that survive central tolerance, maintaining self-tolerance in the periphery.
Answer: CD8+ cytotoxic T lymphocytes (CTLs) are crucial effectors of the adaptive immune system, primarily responsible for identifying and eliminating cells infected with intracellular pathogens (e.g., viruses) and cancerous cells. Their development and function involve a tightly regulated process of activation, differentiation, and targeted killing. **1. CD8+ CTL Activation and Differentiation:** * **Antigen Presentation:** Naive CD8+ T cells are activated primarily by professional antigen-presenting cells (APCs), notably dendritic cells (DCs). DCs process endogenous antigens (e.g., viral proteins) and present them on MHC class I molecules. Crucially, DCs can also acquire exogenous antigens from infected cells and present them on MHC class I via a process called **cross-presentation**. * **Signal 1 (TCR-MHC I Interaction):** The naive CD8+ T cell's T cell receptor (TCR) specifically recognizes and binds to a cognate peptide presented by MHC class I on the APC. The CD8 co-receptor stabilizes this interaction. * **Signal 2 (Co-stimulation):** Concurrently, co-stimulatory molecules on the APC (e.g., B7.1/B7.2) bind to CD28 on the T cell. This signal is essential for full activation and prevents anergy. DCs are particularly effective at providing this signal due to upregulation of B7 molecules upon activation by pathogen-associated molecular patterns (PAMPs). * **Signal 3 (Cytokines):** Activated APCs, particularly DCs, secrete cytokines (e.g., IL-12) that instruct the differentiation of the T cell. Furthermore, IL-2, often initially produced by activated CD4+ helper T cells (which provide 'help' to CD8+ T cells, sometimes via licensing the APC) and subsequently by the activated CD8+ T cell itself (autocrine stimulation), drives the proliferation and differentiation of naive CD8+ T cells into effector CTLs. * **Clonal Expansion and Differentiation:** Upon receiving all three signals, the activated naive CD8+ T cell undergoes extensive clonal expansion, proliferating into a large number of daughter cells. These cells then differentiate into effector CTLs and long-lived memory CD8+ T cells. **2. Mechanisms of Virally Infected Cell Elimination by Effector CTLs:** Effector CTLs migrate to infected tissues and specifically recognize and kill target cells expressing the viral antigen presented on MHC class I. The killing is highly specific and efficient, typically without significant damage to bystander healthy cells. CTLs employ two primary mechanisms: * **Perforin-Granzyme Pathway:** This is the primary and most rapid killing mechanism. * **Binding:** The CTL forms a tight immunological synapse with the target cell, recognizing the viral peptide-MHC class I complex via its TCR and CD8. * **Granule Polarization:** Within minutes, the CTL's cytoplasmic granules (lytic granules containing perforin and granzymes) are rapidly polarized towards the immunological synapse. * **Release of Contents:** Perforin, a pore-forming protein, is released into the synaptic cleft and polymerizes to create channels in the target cell's membrane. This allows granzymes (serine proteases, primarily granzyme B) to enter the target cell cytoplasm. * **Apoptosis Induction:** Granzyme B initiates a cascade of proteolytic events, directly cleaving and activating effector caspases (e.g., caspase-3, -7) and also cleaving Bid (a pro-apoptotic Bcl-2 family member), thereby triggering both extrinsic and intrinsic apoptotic pathways. This leads to DNA fragmentation, chromatin condensation, and ultimately, apoptotic cell death of the infected cell. * **Fas/Fas Ligand (FasL) Pathway:** This is a slower, but equally important, mechanism for inducing apoptosis. * **FasL Expression:** Activated CTLs upregulate the expression of Fas ligand (FasL) on their cell surface. * **Fas-FasL Interaction:** FasL on the CTL binds to Fas (CD95), a death receptor expressed on the surface of many target cells (including virally infected cells). * **Apoptosis Induction:** This binding trimerizes Fas receptors, leading to the recruitment of adaptor proteins (e.g., FADD) and the activation of initiator caspases (e.g., caspase-8). This initiates the extrinsic apoptotic pathway, culminating in the activation of effector caspases and cell death. **3. Significance:** CTLs are capable of serial killing, meaning a single CTL can repeatedly engage and kill multiple infected target cells without itself being destroyed. This efficiency is critical for clearing viral infections and controlling the spread of intracellular pathogens. The specific recognition and targeted apoptosis minimize immunopathology to surrounding healthy tissues.