Lecture 10 - Immunology Study Guide PDF

MHC cell surface proteins present peptide antigens to T cell receptors (TCRs) TCR recognizes both peptide and MHC T cells only recognize protein antigens! MHC = Major Histocompatibility Complex Certainly! Let's break down the process of antigen presentation by MHC cell surface proteins to T cell rec...

MHC cell surface proteins present peptide antigens to T cell receptors (TCRs) TCR recognizes both peptide and MHC T cells only recognize protein antigens! MHC = Major Histocompatibility Complex Certainly! Let's break down the process of antigen presentation by MHC cell surface proteins to T cell receptors (TCRs), focusing on how TCRs recognize both the peptide antigen and the MHC molecule, and how T cells specifically recognize protein antigens: 1. Antigen Presentation by MHC Cell Surface Proteins: MHC molecules, also known as Human Leukocyte Antigen (HLA) in humans, are cell surface proteins that play a crucial role in the immune system by presenting peptide antigens to T cells. There are two main classes of MHC molecules: Class I and Class II. Class I MHC molecules primarily present peptides derived from intracellular proteins to CD8+ cytotoxic T cells, while Class II MHC molecules present peptides derived from extracellular proteins to CD4+ helper T cells. 2. T Cell Receptor (TCR) Recognition: TCRs are specialized protein receptors expressed on the surface of T cells. Each TCR is specific to a particular peptide-MHC complex. The TCR recognizes and binds to the peptide-MHC complex formed by the interaction of the peptide antigen with the MHC molecule. 1 The interaction between the TCR and the peptide-MHC complex is highly specific and plays a central role in initiating T cell responses to pathogens and abnormal cells. 3. TCR Recognition of Peptide and MHC: The TCR recognizes both the peptide antigen and the MHC molecule. The peptide antigen is recognized by the variable regions of the TCR, which form the antigen-binding site. The MHC molecule is recognized by the constant regions of the TCR, providing structural stability to the interaction between the TCR and the peptide-MHC complex. This dual recognition ensures the specificity and fidelity of T cell responses to antigenic peptides presented by MHC molecules. 4. T Cell Recognition of Protein Antigens: T cells specifically recognize protein antigens presented by MHC molecules. Protein antigens are processed and degraded within the cell, resulting in the generation of peptide fragments. These peptide fragments are then loaded onto MHC molecules and presented on the cell surface for recognition by T cells. T cells, through their TCRs, are capable of recognizing a wide range of protein antigens presented by MHC molecules, allowing for the detection and response to various pathogens, infected cells, and cancerous cells. In summary, MHC cell surface proteins play a crucial role in presenting peptide antigens to T cells, allowing for the recognition and response to diverse pathogens and abnormal cells by the immune system. TCRs recognize both the peptide antigen and the MHC molecule, ensuring the specificity and fidelity of T cell responses. T cells specifically recognize protein antigens presented by MHC molecules, initiating immune responses against pathogens and abnormal cells. 1 There are two main classes of MHC cell surface proteins Class I MHCs: Expressed by most nucleated cells Recognized by CD8+ CTLs Class II MHCs: Expressed by APCs Recognized by CD4+ helper T cells Class I MHC molecules: Expressed by most nucleated cells in the body. Primarily involved in presenting peptides derived from intracellular proteins. Recognized by CD8+ cytotoxic T lymphocytes (CTLs), also known as killer T cells. CD8+ T cells, upon recognizing peptide-MHC class I complexes, initiate responses against infected or abnormal cells, leading to their destruction. Class II MHC molecules: Expressed primarily by antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B cells. Involved in presenting peptides derived from extracellular proteins, including those from pathogens engulfed by the APCs. Recognized by CD4+ helper T cells. CD4+ T cells play essential roles in coordinating immune responses by releasing cytokines, providing help to B cells for antibody production, and activating other immune cells such as macrophages. This division of labor between Class I and Class II MHC molecules ensures that the immune system can effectively 2 respond to a wide range of pathogens and abnormalities, both within cells and in the extracellular environment. 2 MHC molecular structure Class I Fully assembled, stable MHC molecule is a trimer Class II The MHC (Major Histocompatibility Complex) molecular structure indeed forms a trimer for both Class I and Class II MHC molecules when they are fully assembled and stable. Class I MHC Molecule: Class I MHC molecules are composed of three main components: an α chain, a β2 microglobulin (β2m) chain, and a peptide antigen. The α chain and β2m chain form the heterodimeric structure, which represents the trimer. The peptide antigen is bound within the peptide-binding cleft of the Class I MHC molecule. Class II MHC Molecule: Class II MHC molecules are also composed of three main components: an α chain, a β chain, and a peptide antigen. The α chain and β chain form the heterodimeric structure, which represents the trimer. Similar to Class I MHC molecules, the peptide antigen is bound within the peptide-binding cleft of the Class II MHC molecule. In summary, the fully assembled and stable MHC molecule, whether Class I or Class II, forms a trimeric structure 3 consisting of the α chain, the β chain (or β2 microglobulin in the case of Class I), and the bound peptide antigen. This trimeric structure is crucial for the proper presentation of peptide antigens to T cells and subsequent immune responses. 3 The peptide-binding cleft contains many polymorphic AAs Variability Greatest Intermediate Least Each MHC cleft binds single peptide at a time but given MHC protein could bind many different peptides Exactly! The peptide-binding cleft of MHC molecules contains numerous polymorphic amino acids, which contribute to the structural diversity within the cleft. This diversity allows MHC molecules to accommodate a wide range of peptide sequences. Although each MHC cleft can only bind a single peptide at a time, a given MHC protein is capable of binding many different peptides over time. This ability stems from the structural flexibility of the MHC molecule and the variability of amino acid residues within the cleft. The versatility of MHC molecules in binding multiple peptides is crucial for the immune system's ability to recognize and respond to a diverse array of pathogens and abnormal cells. By presenting a broad repertoire of antigens to T cells, MHC molecules play a central role in initiating and coordinating adaptive immune responses. 4 The MHC-peptide interaction Interaction is noncovalent Anchor AAs (1-2) fit into pockets in cleft Other AAs interact with walls of cleft Peptide residues recognized by MHC are distinct from those recognized by TCR ChatGPT ChatGPT Certainly! Let's delve into the details of the MHC-peptide interaction: 1. Noncovalent Interaction: The interaction between MHC molecules and peptides is noncovalent, meaning it does not involve the formation or breaking of chemical bonds. Instead, it relies on weaker forces such as hydrogen bonding, van der Waals interactions, and electrostatic interactions. Noncovalent interactions allow for reversible binding between MHC molecules and peptides, enabling the dynamic exchange of peptides on MHC molecules. 2. Anchor Amino Acids and Binding Pockets: Anchor amino acids are specific residues within the peptide sequence that play a crucial role in binding to the MHC molecule. 5 Typically, anchor amino acids are located at positions 1 and 2 of the peptide sequence. These anchor amino acids fit into specific pockets or grooves within the peptide-binding cleft of the MHC molecule. The interaction between anchor amino acids and binding pockets helps stabilize the peptide-MHC complex. 3. Interaction with Walls of the Cleft: In addition to anchor amino acids, other amino acids within the peptide sequence interact with the walls of the peptidebinding cleft. These interactions occur between the side chains of amino acids in the peptide and amino acid residues lining the walls of the cleft. The specificity and strength of these interactions contribute to the overall stability of the peptide-MHC complex. 4. Distinct Recognition by MHC and TCR: The amino acid residues within the peptide sequence that are recognized by the MHC molecule are distinct from those recognized by the T cell receptor (TCR). MHC molecules primarily interact with the anchor amino acids and certain surrounding residues within the peptide. In contrast, TCRs recognize specific regions of the peptide-MHC complex, including both the peptide and the MHC molecule. TCR recognition of the peptide-MHC complex is based on the overall conformation and orientation of the complex, as well as specific amino acid residues within the peptide and the MHC molecule that contribute to TCR binding. In summary, the interaction between MHC molecules and peptides involves noncovalent binding, with anchor amino acids fitting into pockets within the peptide-binding cleft and other amino acids interacting with the walls of the cleft. This interaction is distinct from the recognition of the peptide-MHC complex by TCRs, which involves specific regions of both the peptide and the MHC molecule. The dynamic and specific nature of the MHC-peptide interaction is essential for antigen presentation and T cell activation in the immune response 5 Antigen processing pathway for class I MHC molecules => Where do peptide antigens originate? Class I MHC molecules acquire peptides from cytosolic proteins Possibilities include: Viral proteins Injected microbial proteins Proteins from “escaped” microbes Misfolded host proteins TAP: transporter associated with antigen processing Exactly! Here's a detailed explanation of the antigen processing pathway for Class I MHC molecules: 1. Origin of Peptide Antigens: Peptide antigens presented by Class I MHC molecules originate from cytosolic proteins within the cell. These proteins may include viral proteins synthesized by infected cells, microbial proteins introduced into the cytosol by intracellular pathogens, proteins from "escaped" microbes that have entered the cytosol, and misfolded or abnormal host proteins. 2. Antigen Uptake and Processing: Antigen processing begins with the degradation of intracellular proteins within the cytosol by the proteasome, a large protein complex responsible for protein degradation. The proteasome breaks down proteins into shorter peptide fragments, typically 8-10 amino acids in length. These peptide fragments are then transported from the cytosol into the endoplasmic reticulum (ER) by the Transporter Associated with Antigen Processing (TAP) complex. 3. Major Histocompatibility Complex (MHC) Biosynthesis: While peptide antigens are being transported into the ER, Class I MHC molecules are synthesized and assembled 6 within the ER. Class I MHC molecules consist of a heavy chain (α chain), β2 microglobulin (β2m), and a peptide-binding cleft. The peptide-binding cleft of Class I MHC molecules is initially empty during biosynthesis. 4. Peptide-MHC Association: Within the ER, peptide antigens transported by TAP are loaded onto the newly synthesized Class I MHC molecules. Peptides that bind with high affinity to the peptide-binding cleft of the Class I MHC molecule are selectively retained, while peptides with low affinity are released. Peptide-MHC association ensures that only peptides capable of stable binding to Class I MHC molecules are presented on the cell surface. 5. Class I MHC Pathway and CD8+ CTL Activation: Once peptide antigens are loaded onto Class I MHC molecules, the peptide-MHC complexes are transported from the ER to the cell surface via the Golgi apparatus and secretory vesicles. On the cell surface, the peptide-MHC complexes are displayed for recognition by CD8+ cytotoxic T lymphocytes (CTLs). CD8+ CTLs, equipped with T cell receptors (TCRs) specific for the peptide-MHC complex, recognize and bind to the complex. This interaction triggers activation of the CD8+ CTL, leading to the proliferation and differentiation of effector CTLs, which then target and eliminate cells presenting the specific peptide antigen. In summary, the antigen processing pathway for Class I MHC molecules involves the degradation of cytosolic proteins, transport of peptide antigens into the ER, loading of peptides onto newly synthesized Class I MHC molecules, and presentation of peptide-MHC complexes on the cell surface for recognition by CD8+ cytotoxic T lymphocytes (CTLs). This pathway plays a crucial role in immune surveillance and defense against intracellular pathogens and abnormal cells. 6 Antigen processing pathway for class II MHC molecules => Where do peptide antigens originate? Class II MHC molecules acquire peptides from ingested extracellular proteins Possibilities include: Microbial proteins (endocytosis) Microbes (phagocytosis) Ii prevents loading of cytosolic peptides The antigen processing pathway for Class I MHC molecules involves several steps, ultimately leading to the presentation of peptides derived from cytosolic proteins to CD8+ cytotoxic T lymphocytes (CTLs). Let's break down each step: 1. Antigen Origination: Peptide antigens presented by Class I MHC molecules originate from cytosolic proteins. These proteins can come from various sources, including viral proteins produced within infected cells, microbial proteins injected into host cells by pathogens, proteins from intracellular bacteria that have escaped from phagosomes, and misfolded or aberrant host proteins. 2. Antigen Uptake: Cytosolic proteins are degraded into peptide fragments by the proteasome, a cellular protease complex responsible for protein degradation. The resulting peptide fragments are typically 8-10 amino acids in length and are transported into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP). 3. Antigen Processing: 7 Once in the ER, the peptide fragments are further trimmed by ER-resident peptidases to optimize their length for binding to Class I MHC molecules. The trimmed peptide fragments are loaded onto newly synthesized Class I MHC molecules within the ER. 4. MHC Biosynthesis: Class I MHC molecules are synthesized in the ER and assembled with β2 microglobulin (β2m) and the peptide antigen to form a stable complex. 5. Peptide-MHC Association: The peptide antigen binds to the peptide-binding cleft of the Class I MHC molecule, forming a stable peptide-MHC complex. The specificity of peptide binding is determined by interactions between the anchor amino acids of the peptide and the binding pockets within the MHC molecule. 6. Class I MHC Pathway: The peptide-MHC complex is transported from the ER to the cell surface via the Golgi apparatus. Once on the cell surface, the peptide-MHC complex is displayed for recognition by CD8+ CTLs. CD8+ CTLs, upon recognition of the peptide-MHC complex via their T cell receptors (TCRs), become activated and initiate immune responses against infected or abnormal cells presenting the antigen. In summary, the antigen processing pathway for Class I MHC molecules involves the generation of peptide antigens from cytosolic proteins, their transport into the ER, loading onto newly synthesized Class I MHC molecules, and presentation on the cell surface for recognition by CD8+ CTLs. This pathway plays a critical role in immune surveillance and the elimination of infected or abnormal cells by the adaptive immune system. 7 Every protein antigen contains many potential epitopes => These epitopes are distributed across the peptides produced during antigen processing But the resulting peptides vary in ability to bind the available MHC proteins An individual’s T cells typically respond to a few epitopes (peptides) at most These immunodominant peptides bind to MHC molecules with high affinity Which peptides are immunodominant will vary with which MHC alleles are expressed by the individual ChatGPT ChatGPT Certainly, let's break down the concept of immunodominant epitopes and the factors that influence their selection during antigen processing: 1. Epitopes within Protein Antigens: Epitopes are specific regions on a protein antigen recognized by the immune system. Each protein antigen contains multiple potential epitopes distributed across its sequence. During antigen processing, the protein is broken down into smaller peptides by cellular proteases. 2. Variation in Peptide Binding to MHC Molecules: Not all peptides generated during antigen processing have the same ability to bind to available MHC molecules. The binding affinity of a peptide to a specific MHC allele is influenced by the amino acid sequence of the peptide and the specific polymorphic residues within the MHC binding groove. Some peptides bind with high affinity to certain MHC alleles, while others may have lower affinity or fail to bind 8 altogether. 3. Immunodominant Peptides: Immunodominant peptides are those epitopes that are preferentially recognized by T cells during an immune response. T cells typically respond to a limited number of immunodominant epitopes, even though the original protein antigen may contain many potential epitopes. The selection of immunodominant peptides is influenced by the peptides' ability to bind with high affinity to the available MHC molecules. 4. Role of MHC Alleles: The MHC alleles expressed by an individual play a crucial role in determining which peptides will be immunodominant for that individual. Different MHC alleles have distinct binding specificities, and the presence or absence of certain polymorphic residues within the MHC binding groove affects which peptides can bind effectively. The immunodominance of a particular peptide may vary among individuals with different MHC alleles. 5. Antigen Presentation by Antigen-Presenting Cells (APCs): Antigen-presenting cells (APCs), such as dendritic cells, macrophages, and B cells, play a key role in presenting immunodominant peptides to T cells. APCs internalize antigens, process them into peptides, and present these peptides on their cell surface using Class II MHC molecules. Immunodominant peptides, which bind with high affinity to the Class II MHC molecules, are then recognized by CD4+ helper T cells. 6. T Cell Response: T cells, specifically CD4+ helper T cells, respond to immunodominant peptide epitopes presented by APCs. The interaction between the T cell receptor (TCR) on CD4+ T cells and the immunodominant peptide-MHC complex on APCs initiates signaling cascades leading to T cell activation. In summary, the concept of immunodominant epitopes highlights that not all potential epitopes within a protein antigen elicit a robust T cell response. The selection of immunodominant peptides is influenced by their binding affinity to MHC molecules, and this process varies among individuals based on their specific MHC alleles. The interplay between antigen processing, MHC alleles, and T cell recognition contributes to the specificity and effectiveness of immune responses. 2/2 8 8 T Cell Receptors (TCRs) TCR allows T cell to recognize a specific MHC-peptide complex displayed on either: APC (for class II MHC), or Any nucleated cell (for class I MHC) Each T cell expresses a unique TCR Form multi-protein complex in concert with either/both: Co-receptors: also bind MHC protein Co-stimulators: bind other cell surface protein Recognition initiates signal pathway leading to changes in gene expression Expressed proteins cause T cell activation Certainly, let's delve into the details of T cell receptors (TCRs) and their role in recognizing MHC-peptide complexes and initiating immune responses: 1. Specificity of TCRs: TCRs are expressed on the surface of T cells and play a crucial role in antigen recognition. Each T cell expresses a unique TCR with a specific binding specificity for a particular MHC-peptide complex. TCRs are composed of two protein chains: an alpha chain and a beta chain in the case of αβ T cells, or a gamma chain and a delta chain in the case of γδ T cells. 2. Recognition of MHC-Peptide Complexes: TCRs allow T cells to recognize specific MHC-peptide complexes displayed on the surface of target cells. For CD4+ helper T cells, TCRs recognize MHC class II-peptide complexes presented by antigen-presenting cells (APCs). For CD8+ cytotoxic T cells, TCRs recognize MHC class I-peptide complexes displayed by any nucleated cell in the body. 3. Unique TCR Expression: 9 Each T cell expresses a unique TCR, generated through genetic recombination during T cell development in the thymus. This diversity ensures that the immune system can recognize and respond to a wide range of antigens. 4. Formation of TCR Complex: TCRs form a multi-protein complex on the surface of T cells, working in concert with other proteins. Co-receptors, such as CD4 or CD8, assist in stabilizing the interaction between the TCR and the MHC-peptide complex. CD4 binds to MHC class II, while CD8 binds to MHC class I. Co-stimulatory molecules, such as CD28, provide additional signals that enhance T cell activation and proliferation. 5. Initiation of Signal Pathways: Recognition of the MHC-peptide complex by the TCR initiates signal transduction pathways within the T cell. This leads to activation of intracellular signaling cascades, including phosphorylation events and calcium flux, ultimately resulting in changes in gene expression. 6. T Cell Activation: The expression of specific genes in response to TCR signaling leads to T cell activation and differentiation into effector T cells. Effector T cells carry out various functions, such as releasing cytokines, killing infected or abnormal cells, or providing help to other immune cells. In summary, TCRs play a critical role in the adaptive immune response by allowing T cells to recognize specific MHCpeptide complexes presented by target cells. The unique specificity of TCRs, combined with the formation of multi-protein complexes and the initiation of signal pathways, leads to T cell activation and the coordination of immune responses against pathogens and abnormal cells. 9