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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.

    03:05 Following these positive and negative selection events, the cells switch off expression of either the CD4 or the CD8 gene.

    03:16 If the T-cell had produced a T-cell receptor capable of interacting with MHC Class I, then CD4 is switched off; whereas if the T-cell receptor is capable of interacting with MHC Class II, then CD8 is switched off.

    03:33 So these T-cells now become what we call ‘single positive’ T-cells, in other words, either CD4+ or CD8+.

    03:43 The T-cells then leave the thymus and go to the secondary lymphoid tissues.

    03:50 The diversity of the T-cell receptor is generated by mechanisms that are essentially identical to those that generate the B-cell receptor, in other words, there are a set of T-cell receptor genes that recombine.

    04:12 Here we can see the numbers of gene segments that are involved.

    04:18 For the T-cell receptor α chain, there are 75 Variable gene segments approximately, no Diversity segments, and around about 60 Joining or J gene segments; whereas for the β chain, there are approximately 50 V gene segments, two Diversity gene segments and 13 J gene segments.

    04:43 Regarding the gamma (γ) and delta (δ) T-cell receptor, there are around about 15 V segments, no Ds, five Js; and for the δ chain, eight Vs, three Ds and three 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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