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[Virtual Presenter] Welcome back to the second part of the lecture on the Generation of diversity in T and B cell Receptors. In this part, we will focus on the specific mechanisms involved in generating diversity in B and T cell receptors. These receptors are crucial for the immune system's ability to recognize and respond to pathogens. The diversity generated in these receptors allows for a wide range of specificities to be recognized, making it essential for effective immune responses. We will discuss the main mechanisms involved in generating diversity in B and T cell receptors, including recombination, mutation, and selection. Stay tuned for more information on this important topic..

[Audio] In this part of our lecture, we will discuss the structure of T cell receptors and the mechanisms of diversity generation in T cell receptors. The mechanisms of diversity generation in T cell receptors are similar to those in B cell receptors. We will provide an overview of the T cell receptor structure and the ways in which diversity is generated in T cell receptors..

[Audio] The T cell receptor structure is compared to the antibody. The variable region is the outer part, which is made up of two immunoglobulin domains and is closest to the membrane. It also has a small hinge region and a transmembrane membrane region. The two chains are joined together by a disulphide bond. On the right, we have a comparison of the T cell receptor structure with the antibody structure. The outer fragment, the fab fragment, contains the antigen binding site and is corresponding to the T cell receptor with its antigen binding site in the outer part..

[Audio] The T cell receptor complex is a critical component of the immune system's ability to recognize and respond to foreign antigens. The receptor is associated with signaling polypeptide chains, called the C-D-3 complex, which signals into the cell when the receptor is engaged. When the T cell receptor binds to M-H-C class II, which is the molecule that is recognized by C-D-4 positive T lymphocyte, the C-D-4 molecule will bind to the inner part of the M-H-C class II molecule, located in the more membrane proximal region. This interaction of different surface molecules leads to the activation of the CD4 T helper cell. The C-D-4 molecule brings in intracellular activating proteins and stabilizes the binding between the T cell receptor and M-H-C class II complex. Overall, the T cell receptor complex plays a crucial role in the immune system's ability to recognize and respond to foreign antigens..

[Audio] The organization of the T-cell receptor genes will be discussed. The upper part of the locus is the locus for the T-cell receptor alpha chain. Below that is the locus for the T-cell receptor beta chain. You can see here that the alpha chain corresponds to the light chain because it has a number of V regions, which are illustrated in red. There are also a number of J regions, which are illustrated in green. So the alpha chain only has V and J regions or v j segments, while the beta chain in the lower part has the red segments, which are the V segments. It also has the D for diversity segments and the J segments. And then for both alpha and beta chain, you also have the blue, constant uh gene segments. The variable antigen binding sites of the T cell receptor are also made up of the D and J segments. And then you have the constant region, which is C in the illustration. So the alpha chain is made up of the V plus the J together with a constant segment. And the beta chain is made up of a rearrangement between v, d and j plus the constant segment..

[Audio] We discuss the generation of diversity in B and T cell receptors. The slide shows the recombination of T-cell receptor genes. We examine the beta chain rearrangement, which is similar to the heavy chain in B-cells. The germline DNA, V and J segments, and rearrangement process are shown. The rearranged D-N-A is transcribed, spliced, and translated into the T-cell receptor beta chain. We move on to the upper part of the slide and see the corresponding process for the alpha chain. The V and j are directly joined, followed by transcription, splicing, and translation to form the T alpha chain protein. That's it! The T-cell receptor genes are rearranged to generate diversity in B and T cell receptors..

[Audio] Here, you see the diversity of T-cell receptor. We calculated the diversity of the alpha beta T-cell receptor by looking at the number of segments and then the combinatorial diversity and the junctional diversity. You see that there are two D segments in the beta chain, none in the alpha. And then you have the joining the J segments of the alpha and the beta chain. Those together amount to about three times ten. If this variability together amounts to about three times ten to the six different receptors, but if you add the junctional diversity, which we talked about before, you can see that the variability of the T cell receptor is actually as high as ten to the 16. So the theoretically possible cell diversity is around ten to the 11. And when it comes to T cells, this is actually even higher. So both the T cell receptors and the B cell receptors have an enormous diversity that can be expressed on the population level..

[Audio] T cell receptors (TCRs) are created through the combination of different V(D)J segments, the addition and removal of nucleotides at the edges of the gene segments, and the combination of different alpha and beta chains. This variability in T cells is created in the thymus independently of foreign antigen. T cells do not undergo somatic hypermutation..

[Audio] We continue with the second part of the lecture, which focused on the generation of diversity in B and T cell receptors. Next, you will see that there are T cell subsets that have less variable receptors. One example is gamma delta T cells, which express a gamma and a delta chain in their T cell receptor. These T cell receptors are homologous but different protein chains in their T cell receptors. Another example is natural killer T cells, a subset of alpha beta T cells, which have T cell receptors with limited variability. They do not have the same diverse repertoires as conventional T cells. Additionally, these T cell receptors do not bind to antigen presented on normal M-H-C molecules..

[Audio] T lymphocytes development is a complex process that occurs in the thymus, a specialized organ located above the heart and lungs. The thymus supports the maturation of T lymphocytes, and the illustration shows a cross-section of the thymus, which includes the upper part, called the cortex, and the lower part, called the medulla. As the maturing T lymphocytes move through the different regions of the thymus, they undergo various processes of thymocyte development, including recombination of T-cell receptor genes, positive and negative selection, and lineage decision. All these steps occur within the thymus, and we will discuss them in detail in the upcoming lecture..

[Audio] We are discussing T cell development in the thymus. T cells are a type of white blood cell that play a critical role in the immune system. They are responsible for recognizing and eliminating invasive pathogens, such as viruses and bacteria..

[Audio] We will discuss the T-cell selection process, which ensures that T-cell receptors are functional and non-harmful. Positive selection selects T cells that can bind to MHC-peptide complexes in the thymus, which are essential for immune function. Negative selection eliminates T cells that bind too strongly to MHC-peptide complexes in the thymus. These cells are self-reactive and can cause harm to the body. Negative selection ensures that the T cell receptor repertoire is functional and non-harmful, allowing cells to leave the thymus and be ready for engagement in immune responses. In summary, the T-cell selection process plays a crucial role in shaping the final T cell receptor repertoire. Positive selection selects T cells with functional T-C-R-s-, while negative selection eliminates self-reactive T cells. This ensures that the T cell receptor repertoire is functional and non-harmful, allowing cells to leave the thymus and be ready for engagement in immune responses..

[Audio] T-cell precursor cells move from the bone marrow and start to recombine the T-cell receptor genes, generating a diverse population of T cells that can recognize and respond to a wide range of pathogens. Immunature T-cells go through positive and negative selection, with successful cells moving out into the periphery to recirculate through the blood and lymphoid organs and be ready to meet their antigen. Once activated, the T-cell leaves the lymphoid organs and goes back to the site of infection, performing different effector functions. This process is essential for the immune system to function properly and protect the body from infections and diseases..

[Audio] Anetta Härtlova from the Department of Microbiology and Immunology presented a lecture on the generation of diversity in B and T cell receptors. She explained that the B cell receptor and the T cell receptor consist of heavy and light chains that are built up by variable and constant regions. The variable antigen binding sites of T cell receptors and B cell receptors are made up of A, V, D, and J segments. The heavy chain has the D segment, while the beta chain has the alpha segment. The enormous diversity of this variable antigen binding sites is created in the bone marrow for B cells and the thymus for T cells by the recombination of V(D)J gene segments, unprecise ligation of these segments, and then final combination of the two types of receptor chains. This process is not dependent on the presence of foreign antigens..