PHARM 310 - LEC 4 - Lymphocytes and Immune Response

Lymphocyte Development

• Lymphocytes, specifically B and T cells, originate from the same lineage in the bone marrow.
• B cells are formed in the bone marrow and responsible for antibody production; T cells migrate to the thymus to develop further.

Structure and Function of T Cell Receptors

• T cell receptors (TCR) consist of an alpha chain and a beta chain, linked by disulfide bonds.
• TCR has a single binding site for antigens, unlike antibodies, which have two binding sites.
• TCRs recognize peptide antigens presented by major histocompatibility complex (MHC) molecules.

Major Histocompatibility Complex (MHC)

• MHC molecules are present on almost all nucleated cells but not on erythrocytes.
• MHC molecules play a crucial role in tissue compatibility; MHC incompatibility can lead to graft rejection and graft-versus-host disease during transplants.

T Cell Diversity

• T cell receptor gene diversity is generated through a rearrangement process involving the RAG enzyme complex.
• Gene segments for TCRs are scattered across specific chromosomes (e.g., 14, 7, 2, 22).
• Each T cell ultimately expresses a unique TCR due to gene rearrangement.

Accessory Proteins in T Cells

• TCRs require accessory proteins called the CD3 complex to facilitate signaling upon antigen binding.
• The CD3 complex consists of gamma, delta, epsilon, and zeta chains, critical for T cell activation.

Types of T Cells

• TCRs are classified as either alpha-beta TCRs or gamma-delta TCRs.
• Gamma-delta T cells form less than 5% of the total T cell population and are involved in cancer surveillance.

Antigen Processing and Presentation

• TCRs can only recognize antigens as peptide fragments presented by MHC molecules.
• Pathogen-derived proteins are processed inside cells to generate peptide fragments that bind to MHC molecules for display.

MHC Classes

• MHC Class I is present on all nucleated cells and interacts primarily with CD8 cytotoxic T cells.
• MHC Class II is found only on professional antigen presenting cells (APCs) such as dendritic cells and B cells and interacts with CD4 helper T cells.

T Cell Activation

• The interaction between TCRs and MHC-peptide complexes is stabilized by co-receptors: CD4 for T helper cells and CD8 for cytotoxic T cells.
• Helper T cells (CD4) assist in activating macrophages and B cells, while cytotoxic T cells (CD8) directly target and kill infected cells.

Professional Antigen Presenting Cells (APCs)

• Dendritic cells are the most efficient APCs, followed by macrophages and B cells.
• APCs load antigens onto MHC Class I or II for presentation to T cells.

Degenerate Binding Specificity of MHC

• MHC molecules exhibit degenerate specificity, enabling them to bind various peptide shapes and charges.
• This broad binding capability allows MHC to present a diverse array of antigens to T cells.

Intracellular Compartments and Antigen Loading

• Cells have two main compartments: the cytosol (internal fluid) and the vesicular system (membrane-bound structures).
• Antigens are sampled via endocytic vesicles, which then merge with lysosomes or the endoplasmic reticulum for MHC loading.

Summary of MHC and TCR Interactions

• MHC class I presents endogenous antigens to CD8 T cells; MHC class II presents exogenous antigens to CD4 T cells.
• This interaction is crucial for the immune response, determining whether T cells will help other immune cells or directly kill infected cells.### Antigen Presentation and T Cell Activation
• Infected cells express viral or cancer antigens on their surface to signal cytotoxic T lymphocytes for destruction.
• MHC Class I molecules, present on all nucleated cells, present endogenous antigens (self or viral) to CD8 T cells.
• MHC Class II molecules, found only on professional antigen-presenting cells (APCs) like dendritic cells and macrophages, present exogenous antigens to CD4 T helper cells.

Lymphoid Organs

• Primary lymphoid organs: bone marrow and thymus.
• Secondary lymphoid organs: lymph nodes, spleen, and other aggregates of lymphoid cells.
• APCs sample exogenous antigens, process them, and present them via MHC Class II in the lymphoid tissues.

MHC Class I Mechanism

• Viral proteins in infected cells are degraded by the proteasome into peptide fragments, which are transported to the endoplasmic reticulum (ER).
• Peptide editing occurs to ensure only high-affinity peptides bind to MHC Class I before being presented on the cell surface to CD8 T cells.

MHC Class II Mechanism

• Extracellular pathogens are internalized through endocytic vesicles, which then fuse with lysosomes containing enzymes to degrade them into peptides.
• Invariant chain blocks premature peptide binding in the ER and guides MHC Class II to lysosomal compartments where it eventually binds to pathogen-derived peptides after HLA-DM activity.

Diversity of MHC Molecules

• MHC genes exhibit polymorphism, generating diversity among individuals through genetic variations and mechanisms like meiotic recombination.
• Six MHC Class I isotypes: A, B, C, E, F, G.
• Five MHC Class II isotypes: DM, DP, DQ, DR, DO.

MHC Restriction

• T-cell receptors recognize both the presented peptide and the MHC molecule, necessitating congruence for T cell activation.
• Failure to match either the peptide or the MHC receptor results in no T cell activation.

Antigen-Processing Cells and Homing

• Dendritic cells and macrophages transport processed antigens to secondary lymphoid tissues via lymphatics, allowing interaction with T lymphocytes.
• Adhesion molecules facilitate the movement of lymphocytes into lymph nodes from the bloodstream, allowing targeted immune responses.

Key Vocabulary

• Cytotoxic T lymphocytes: Immune cells that kill infected cells.
• CD4/CD8 T cells: Subtypes of T lymphocytes that interact with Class II/Class I MHC molecules, respectively.
• Peptide editing: Process of ensuring stable peptide-MHC binding.
• Invariant chain: Protein that prevents premature peptide binding to MHC Class II in the ER.### Lymphocyte Migration and Activation
• Lymphocytes migrate into lymphoid tissues by rolling on endothelial cells and adhering tightly through adhesion molecules.
• Professional antigen-presenting cells (APCs) like dendritic cells sample antigens in infected tissues and transport them to lymph nodes.
• In lymph nodes, dendritic cells present antigens to naive T cells on Major Histocompatibility Complex (MHC) class II molecules.

Antigen Presentation and Costimulation

• Dendritic cells, macrophages, and B cells act as APCs, with dendritic cells being the most effective at antigen presentation.
• Costimulatory molecules, like B7, on APCs are essential for T cell activation alongside MHC molecule binding.
• Immature APCs express few MHC and costimulatory molecules, limiting their ability to activate T cells.

T Cell Activation Process

• T cell activation requires two signals: specific recognition of the antigen by the T cell receptor and a costimulatory signal from the APC.
• Activated T cells proliferate and differentiate; Interleukin-2 (IL-2) plays a crucial role in this process by promoting T cell growth and survival.
• Absence of costimulation leads to an anergic state, rendering T cells unresponsive to antigens.

Mechanisms of T Cell Activation

• B cells also present antigens: they bind specific antigens, internalize them, and present them on MHC class II molecules to activate T cells.
• Three activation mechanisms for cytotoxic T cells include autocrine IL-2 signaling, costimulatory signals from helper T cells, and paracrine signaling from adjacent activated cells.

Cytotoxic T Cell Function

• Cytotoxic T cells induce apoptosis in infected target cells using death-domain ligands (e.g., FAS) and release perforin and granzymes.
• Perforin creates pores in target cell membranes, while granzymes initiate the degradation of cell structures to promote cell death.

Distinctions in Cell Death

• Apoptotic cells undergo a clean, non-inflammatory process, contrasting with necrotic cells that release pro-inflammatory signals due to cellular lysis.
• Apoptosis is characterized by chromatin condensation and vesicle formation, allowing for a tidy disposal of the dying cell without triggering inflammation.

T Helper Cell Functions

• CD4 T helper cells differentiate into subsets (e.g., Th1 and Th2).
• Th1 cells primarily activate macrophages and promote pro-inflammatory responses.
• Th2 cells are involved in B cell activation and antibody production.

Immune Regulation Mechanisms

• CTLA-4, an important receptor on T cells, competes with CD28 for binding to B7, downregulating T cell activation after an immune response.
• Effector T cells produce varied effector molecules, with CD8 T cells focused on cytotoxic functions and CD4 T cells on helper roles for macrophages and B cells.