B and T Cell Receptors and Clone Selection - PDF Lecture Notes

The B- and T-cell receptors, Clone selection Dóra Boros-PÁL  Cell receptors and their soluble form, antibodies, as well as T cell receptors, are glycoproteins → that exist in each person in an amount that far exceeds the diversity of pathogens. Each receptor is responsible for...

The B- and T-cell receptors, Clone selection Dóra Boros-PÁL  Cell receptors and their soluble form, antibodies, as well as T cell receptors, are glycoproteins → that exist in each person in an amount that far exceeds the diversity of pathogens. Each receptor is responsible for recognizing only one pathogen. Together, the billions of types of receptors are capable of specifically recognizing every pathogen.  Light chain B cell receptor: Disulphide Symmetric molecule bridge It has 4 protein chains, of which 2 are light Heavy chains and 2 are heavy chains chain The chains consist of constant and variable sequence domains Light chain: 1 variable + 1 constant domain Heavy chain: 3 or 4 constant + 1 variable domain The chains are connected by disulfide bridges, which are formed between cysteine amino acids  Y-shaped structure Variable domains at the ends of the forks → create the antigen binding site The stem of the Y-shaped structure is the constant domain, which provides the spatial stability of the molecule and certain effector functions  Based on the variability of the constant domain → 5 main types of heavy chains are distinguished, which are the following: IgM, IgD, IgG, IgA, IgE. There are 2 types of light chains: ĸ and λ. The receptor has two identical antigen-binding sites → allowing it to form a bivalent interaction with the appropriate antigen.  The immunoglobulin molecule during the immune response: Soluble form: BCR: Produced by plasma cells Located on the surface of B cells Secreted by the cells into the extracellular space Has a transmembrane region Structurally identical to the cell surface It is associated with other membrane- immunoglobulin molecule anchored signaling chains → it transmits Recognizes the same antigen as the original activating signals to the cell. BCR Lacks the transmembrane region, so it does not connect to a signaling chain  T Cell Receptor (TCR) In terms of structural properties, it is similar to the antibody molecule The antigen-recognizing part consists of two chains → Each chain is composed of one constant domain and one variable domain Disulfide bridges form between cysteine amino acids → within and between the chains The two variable domains together are responsible for recognizing the antigen → the MHC-peptide complex The constant domains mainly have a structure-stabilizing function It has a membrane-anchoring region Covalently linked to the signaling chain TCR has only one antigen-binding site A soluble form of the molecule does not form  Clonal Division of B Cells In the bone marrow, 10 million to 1 billion B cells are formed daily. Naive B lymphocytes create antibodies through gene translocation → resulting antibodies that have a unique antigen-binding site (Fab). The antibody molecules are presented on the surface of B cells as B cell receptors, capable of reacting with the epitopes of an antigen. They express unique antigen-recognizing receptors with distinct specificities on their cell surface. Each lymphocyte displays approximately 100,000 receptors, but each one has the same specificity, meaning that a single cell is specialized to recognize only one type of antigen.  Lymphocyte Individuals Recognizing Own Structures / Various Possible Pathogen Antigens Are Formed Daily Lymphocytes that recognize their own structures with high "intensity" → are destroyed in the early phase. This prevent self-recognizing autoimmune lymphocytes entering the periphery → this process known as → central tolerance.  After maturation occurring in the primary immune organs, → they enter the bloodstream, → where they exit into the secondary lymphoid organs and begin searching for the antigens they can recognize. If they do not encounter their specific antigen, → they continue to migrate through the lymphatic and circulatory systems to other lymph nodes/secondary lymphoid tissues → checking their antigen repertoire.  Primarily, they encounter foreign antigens in secondary lymphoid tissues. “Foreign substances” that enter the peripheral lymphoid organs interact with the lymphocyte repertoire → that has entered the circulation from the bone marrow. The epitopes of the antigen ultimately react with those B lymphocytes whose surface B cell receptors fit them well. This interaction activates these B lymphocytes. This process is called clonal selection.  The cytokines produced by effector T helper (T4) lymphocytes → facilitate the rapid proliferation of activated B lymphocytes, → resulting in the formation of a clone consisting of thousands of identical B lymphocytes. During proliferation, they also undergo affinity maturation, which is the result of somatic hypermutations. Affinity maturation → allows B lymphocytes to refine the shape of their antibodies to better fit the original epitope. B lymphocytes with surface B cell receptors that fit better → bind to the epitope for a longer time and more tightly → enabling these cells to replicate selectively.  B lymphocytes differentiate into antibody-producing plasma cells, which secrete a massive amount of antibodies that fit the original epitope. Some B lymphocytes differentiate into B memory cells, which are capable of mounting an anamnestic response. Generally, it takes about 4-5 days for an activated naive B lymphocyte to complete clonal expansion and differentiate into an effector B lymphocyte. A single activated B lymphocyte can generate approximately 4,000 antibody-producing cells within a week. A plasma cell can produce more than 2,000 antibody molecules per second. Once the pathogen is destroyed, the disappearance of the antigen renders the pathogen- specific clones redundant, leading to their destruction by apoptosis in the final stage of the immune response.  Clonal Division of T Cells 1. Antigen Recognition: The T cell receptor encounters an antigen-presenting cell (APC) that presents a fragment of the pathogen on its cell surface. The TCR recognizes the specific antigen presented by the APC. 2. T Cell Activation: The TCR specifically binds to an antigen, thereby activating the T cell. 3. Clonal Division: The activated T cell undergoes rapid division, resulting in the production of a large number of clones that possess the original T cell's specific TCR. 4. Formation of Effector and Memory Cells: During clonal division, two types of T cells are generated: Effector T Cells: Directly involved in combating the infection. CD8+ cytotoxic T cells destroy infected cells. CD4+ helper T cells activate other immune cells. Memory T Cells: Remain in the body for a long time and respond more quickly if the same infection reappears, providing immunological memory. 5. Termination of the Response: After the successful elimination of the infection, apoptosis occurs in the effector T cells. The memory cells remain, ready for another infection. Thank you for your attention!