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T-Cell Development in Thymus and Genetic Recombination of TCR – Lymphocyte Development

by Peter Delves, PhD

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    00:01 Let’s now look in a little bit more detail about the actual development process in the thymus.

    00:07 We’ve heard that the T-cells migrate through the cortex and into the medulla.

    00:11 So exactly what’s going on during those migration processes? Well when the T-cells first enter the thymus, having come from the bone marrow, they lack expression of two molecules - CD4 and CD8.

    00:28 We therefore refer to them as being CD8 negative (CD8-), CD4 negative (CD4-).

    00:34 And immunologists use a bit of jargon that’s called ‘double negative T-cell’.

    00:38 So if you hear an immunologist talk about double negative T-cells, you wouldn’t know what on earth they were talking about. But what they’re actually referring to is cells that are CD4-, CD8-, lacking both of those molecules. Shortly after arrival in the thymus, the genes for both of those molecules are switched on and these T-cells become CD4 positive (CD4+), CD8 positive (CD8+); in other words in the jargon, ‘double positive T-cells’. These are now ready to undergo thymic education.

    01:11 And the first step in thymic education which takes place in the cortex is interactions of the T-cells with thymic epithelial cells.

    01:20 And the purpose of this interaction is to ensure that the T-cell receptor that has been generated by random recombination is able to recognize our own MHC variants.

    01:34 It’s no good if the T-cell receptor can’t recognize MHC because we’re talking about alpha beta (αβ) T-cells here.

    01:40 They need to recognize peptide presented by MHC.

    01:43 They need to recognize peptide presented by our own variants of the MHC, not somebody else’s variant.

    01:49 So the first stage in thymic education is called positive selection.

    01:55 And T-cells are selected positively if they are able to recognize peptides presented by our own MHC molecules.

    02:04 If they fail to do so, they die by apoptotic cell death.

    02:10 So, positive selection rescues from apoptosis, cells that recognize ‘self’ MHC.

    02:21 This is followed by negative selection, where there is induction of apoptosis if the T-cells recognize autoantigens, in other words, self antigens.

    02:33 And this process constitutes what we refer to as central tolerance.

    02:37 We say that immune cells, and we’re referring here specifically to lymphocytes; that the lymphocytes become tolerant to self antigens.

    02:46 They don’t react to self antigens.

    02:48 And this negative selection in the thymic medulla, where the T-cells interact with dendritic cells and macrophages that are showing self antigens to the T-cells, if there is recognition of these self antigens, apoptosis is induced and those cells are got rid of.

    03:06 If the T cell had produced a T cell receptor capable of interacting with MHC class 1, then CD4 is switch off.

    03:16 Whereas, if the T cell receptor is capable of interacting with MHC class 2, then CD8 is switched off.

    03:23 So these T cells become what we call single positive T cells, in other words either CD4 positive or CD8 positive.

    03:33 The T cells then leave the thymus and go to the secondary lymphoid tissues.

    03:40 The diversity of the T cell receptor is generated by mechanisms that are essentially identical to those that generate the B cell receptor.

    03:51 In other words, they are a set of T cell receptor genes that recombine.

    03:58 Here we can see the numbers of gene segments that were involved.

    04:07 For the T cell receptor alpha chain there are 75 variable gene segments approximately, no diversity segments, and around about 60 joining or J gene segments.

    04:21 Whereas, for the beta chain, there are approximately 50 V gene segments, two diversity gene segments, and 13 J gene segments.

    04:33 Regarding the gamma delta T cell receptor, there are around about 15 V segments, no Ds, 5 Js.

    04:45 And for the delta chain, 8 Vs, 3 Ds and 3 Js.


    About the Lecture

    The lecture T-Cell Development in Thymus and Genetic Recombination of TCR – Lymphocyte Development by Peter Delves, PhD is from the course Adaptive Immune System. It contains the following chapters:

    • T-Cell Development in the Thymus
    • Genetic Recombination of TCR Genes

    Included Quiz Questions

    1. Cluster of differentiation 4 and cluster of differentiation 8
    2. αβ T-cell receptors and γδ T-cell receptors
    3. Pathogen-associated molecular patterns and damage-associated molecular patterns
    4. Major histocompatibility complexclass I and major histocompatibility complexclass II
    5. Cluster of differentiation 1 and cluster of differentiation 3
    1. Positive selection: T cells that recognize and bind MHC class I or II molecules are selected.
    2. Positive selection: T cells that recognize and bind MHC class I or II molecules undergo apoptosis.
    3. Positive selection: T cells become double positive.
    4. Negative selection: T cells that recognize and bind MHC class I or II molecules undergo apoptosis.
    5. Negative selection: T cells that recognize and bind MHC class I or II molecules are selected.
    1. Induction of apoptosis in thymocytes with a high affinity for self peptides or major histocompatibility complex
    2. Selecting cells with a T cell receptor able to bind major histocompatibility complex class I or II molecules
    3. Eliminating T cells which would be non-functional due to an inability to bind major histocompatibility complex
    4. Eliminating thymocytes with gross defects introduced into the T cell receptor by gene rearrangement
    5. Silencing thymocytes with gross defects in cell surface receptors in the peripheral blood

    Author of lecture T-Cell Development in Thymus and Genetic Recombination of TCR – Lymphocyte Development

     Peter Delves, PhD

    Peter Delves, PhD


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    awesome
    By asha bashir n. on 16. April 2021 for T-Cell Development in Thymus and Genetic Recombination of TCR – Lymphocyte Development

    perfect and easy to follow, and friendly lecture, so far the best teacher