In this episode, Killer T Cell trains a group of Naïve T Cells while Helper T Cell and Regulatory T Cell work in the office. However, when Killer T Cell throws Naïve T Cell which hits Helper T Cell, Killer T Cell and Helper T Cell argue with each other. In the meantime, Dendritic Cell tells a story to Naïve T Cells on how Killer T Cell and Helper T Cell met while they were thymocytes in the thymus. While Helper T Cell easily passes the training exercises, Killer T Cell barely manages to keep up. With the advice of Helper T Cell; however, Killer T Cell manages to pass his final exam. Before leaving the thymus, Killer T Cell and Helper T Cell make promises to each other, with the former vowing to get stronger and the latter deciding to become a commander to coordinate other immune cells.

How do T cells really develop in the thymus? Join us as we go inside the thymus to describe what thymocytes go through to become mature T cells.

A brief primer on T cells

Schematic	Microscopic	Anime
		Killer T cell	Helper T cell	Regulatory T cell

T cells are white blood cells that are present in both blood and tissues around the body. They are characterised by a T cell receptor that consists of two chains: an α and a β chain. There are three main subtypes of T cells:

• Killer T cells identify and kill cells in the human body that are infected by intracellular bacteria or viruses, transformed into cancer cells or derived from another person (such as an organ transplant).
• Helper T cells amplify the numbers and functions of other immune cells such as macrophages and B cells by interacting with other immune cells and secreting cytokines.
• Regulatory T cells suppress immune responses, particularly after infection is resolved. They do this through many ways such as suppressing cell function and secreting immunosuppressive cytokines.

Thymus: the site for T cell development

The thymus is a bilobed organ located in between the lungs, behind the sternum and above the trachea and heart. The thymus is where immature T cells called thymocytes develop into mature T cells. The thymus is sectioned into lobules which give the thymus a “bumpy” appearance. Each lobule contains two regions: the outer cortex and the inner medulla. These regions are where thymocytes undergo different steps to produce a T cell receptor that allows T cells to respond to infections without attacking their own cells.

Schematic	Microscopic	Anime

The thymus consists mostly of thymic epithelial cells (TECs) as depicted by Thymic Epithelial Cell Instructor in the episode. Other cells are also present in the thymus such as dendritic cells (DCs), mesenchymal cells and endothelial cells. TECs secrete a wide array of cytokines and chemokines to maintain an environment where thymocytes can survive, develop and proliferate. TECs and DCs also express self-antigens found all around the human body to select functional T cells that will not react and attack the body’s own cells.

Did you know? The thymus is large at birth and reaches its biggest size during puberty. However, ageing progressively reduces the size and cell numbers of the thymus. At old age, the thymus is very small and mostly contains fat, limiting T cell production. This increases the risk of the elderly to contract infections.

Generating a T cell receptor in the thymus

Thymocytes are derived from haematopoietic stem cells in the bone marrow. They migrate to the thymus where they enter the organ via the corticomedullary junction. They first travel to the cortex where they receive signals that commit them to become T cells. At this stage, thymocytes do not have a T cell receptor or co-receptors CD4 or CD8 and have not committed to a specific T cell subset (helper, killer or regulatory T cell).

RAG1/2 (Recombination Activating Gene) enzymes inside the thymocyte are activated to rearrange, recombine and mutate gene segments relating to the generation of α and β chains of the T cell receptor. Individual thymocytes will generate different T cell receptors that react to different antigens. Chains of the T cell receptor then try to travel to the surface. If the T cell receptor fails to emerge on the surface of the thymocyte, the cell dies by apoptosis. However, if the T cell receptor successfully emerges on the thymocyte surface, it produces survival signals that allow the thymocyte to live. The thymocyte also shows both CD4 and CD8, becoming a double positive T cell.

Positive selection: picking functional T cells

Contrary to the anime episode, double positive T cells do not try to recognise infected cells in the thymus. Instead, they interact with self-antigens from the human body produced and presented on MHC complexes by thymic epithelial cells (TECs) in the thymic cortex. Positive selection describes the survival signals T cells receive if their T cell receptor weakly binds to the antigen-MHC complex on TECs. If the T cell receptor cannot bind to the antigen-MHC complex at all, the T cell will be unable to recognise foreign antigens during infection. As a result, the thymocyte does not receive survival signals and dies by neglect. Double positive T cells pass positive selection by continually surveying various antigen-MHC complexes on TECs to receive survival signals from them.

During positive selection, double positive T cells become single positive T cells. They commit to becoming a CD4⁺ or CD8⁺ T cell which correspond to helper and killer T cells respectively. This is dependent on which MHC complex the T cell receptor and its co-receptor engages more strongly.

• If the double positive T cell more strongly recognizes self-antigen on the MHC class I complex, it will become a CD8⁺ T cell (expressing CD8 only), committing them to become a killer T cell when activated.
• If the double positive T cell more strongly recognizes self-antigen on the MHC class II complex, it will become a CD4⁺ T cell (expressing CD4 only), committing them to become a helper T cell when activated.

Negative selection: weeding out autoreactive T cells

Surviving single-positive T cells move to the medulla of the thymus, where they are exposed to a wider array of self-antigens from different tissues produced and presented by TECs and DCs. Negative selection involves identifying single-positive T cells whose T cell receptor binds too strongly to the antigen-MHC complex on TECs and thymic DCs. These cells die by apoptosis (represented by the T cell dropping into the chute after attacking a healthy cell in the episode). This removes autoreactive T cells that would have attacked its own cells and tissues if they are activated. The failure of removing autoreactive T cells is the basis of some autoimmune diseases such as type I diabetes and multiple sclerosis.

Did you know? In the medulla, regulatory T cells are produced when CD4⁺ T cells moderately bind to the antigen-MHC complex (though not strong enough to kill them) and receive signals from DCs (such as IL-2 and CD80/86) that prompt them to become regulatory T cells (by expressing factors such as CD25 and FoxP3).

Summary

The harsh training T Cells received in the thymus reflects what happens in real-life. Thymocytes enter the thymus, initially developing a T cell receptor that emerges on the thymocyte surface. They then become double positive T cells, expressing CD4 and CD8, and undergo positive and negative selection. Positive selection provides survival signals to cells whose T cell receptor can interact with antigen-MHC complexes in TECs. Negative selection, in contrast, kills T cells that bind too strongly to antigen-MHC complexes on TECs and DCs. Both processes are essential for picking out T cells that will leave the thymus and respond to infections or cancers by reacting to foreign antigens. At the same time, these cells will not attack its own cells and tissues, preventing autoimmune diseases from occurring. Together, different T cell subsets act to defend the human body against infections, cancers and other threats while maintaining a healthy state where healthy cells are left alone.

In the next blog post, we will look at a common bacterial infection and see how the body responds to it. See you then!