T Cell Development and Maturation in The Thymus Simplified

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The study of T cell development from the bone marrow through the thymus and finally into peripheral blood circulation remains an important topic in immunology. An understanding of this development is crucial to doctors who treat diseases relating to the failure of the immune system.

Moreso, T-cell development is important to immunologists and other scientists working on immunotherapy (enhancing immune cells to work better). Remember the T cells are like the cornerstone of your adaptive immunity.

Without T cells, it would be impossible to successfully fight off any infections because they also help other immune cells to do their work. This article discusses the journey of T cells from the bone marrow until they exit the thymus as naïve CD4+ or CD8+ mature T cells into your blood circulation.

T cell Development in the Bone Marrow

The T cell also called T lymphocyte begins its development in the bone marrow as a hematopoietic stem cell. This common stem cell differentiates into a common myeloid progenitor and a common lymphoid progenitor. The latter is what further develops to become the T cells, the B cells, and natural killer cells.

The developing T cells exit the bone marrow and go via the bloodstream to the thymus where they complete their development. Therefore, in the bone marrow, there is nothing much that happens with regard to T cell development.

The Development of T Cells in the Thymus

The thymus is a primary lymphoid tissue that supports T cell development in your body. Experiments that have been conducted with athymic mice have underscored the importance of this primary lymphoid organ in naturing the T cells to maturity. Athymic mice are unable to develop mature functional T cells.

In your body, the thymus is anatomically located mid-sternum within the chest cavity. It is most active during childhood and shrinks in size after puberty in most individuals since their immune systems are fully developed by then. 

You don’t need your thymus much in adulthood because you already have enough T cells in your peripheral circulation to help you fight antigens. The developing T cells enter your thymus as double negative cells (without CD4 and CD8 co-receptors).

They enter via the cortex which is the outer region of the thymus before they can get deeper into the medulla of your thymus as they develop. These cells are now called thymocytes because of their association with the thymic microenvironment.

Double Negative Stages of T cell Development

Scientists have classified the double negative (DN) stages into four. That is DN1, DN2, DN3, and DN4 stages. Each of the four stages is identified by the presence of some markers and the absence of others on the thymocytes’ surface. As already mentioned earlier the DN stages are named so because thymocytes lack both the CD4 and CD8 markers (co-receptors) on their surface.

Double Negative 1 (DN1) Stage

The thymocytes in this stage develop in the cortical region of the thymus. These cells express adhesion molecule CD44, and another protein called c-kit on their surface.  These cells lack the CD25 marker also called the interleukin-2 receptor (IL-2R) on their surface.

As expected, the DN1 thymocytes do not express CD4 and CD8 markers on their surface. Therefore, the DN1 T cells are in summary c-kit⁺CD44⁺CD25^–CD4^–CD8^– T cells. These cells at this point are yet to express the T cell receptor (TCR).

Double Negative 2 (DN2) Stage

This is the second stage of development of the thymic T cells. The biggest advancement of thymocytes at this stage compared to the previous DN1 stage is the expression of the CD25 marker on their surface.

Therefore, in summary, we can say that the DN2 T cells are c-kit^–CD44⁺CD25⁺CD4^–CD8^– T cells. The other important point you need to note is that these cells are yet to begin re-arranging the genes for the TCR and so they do not express the T cell receptor.

Double Negative 3 (DN3) Stage

At this stage of T cell development, the thymocytes lose their expression of the cell adhesion molecule CD44 and upregulate expression of the IL-2R i.e CD25. These thymocytes further begin to re-arrange the beta (β) genes responsible for the β-chains of αβTCR.

Therefore, at this point, we can begin to see that the developing T cells can express the pre-TCR that will be important later in the signal transduction process of the re-arrangement of the alpha (α) genes. The DN3 thymocytes can be represented in terms of their identity markers as c-kit^–CD44^–CD25⁺CD4^–CD8^–T cells.

Double Negative 4 (DN4) Stage

The fourth and last stage of the double negative thymocytes is the DN4 stage. These thymocytes do not express the CD25 and hence cannot bind IL-2 as CD25 is the IL-2R. The DN4 also lacks CD44 and the c-kit molecule.

This stage of T cell development is pre-TCRβ dependent and so it cannot happen without properly re-arranged β-chains of the T cell receptor. Therefore, the DN4 cells can be represented in terms of markers as c-kit^–CD44^–CD25^–CD4^–CD8^– T cells.

Double Positive (DP) Stage of T cell Development

Thymocytes in the DP stage are named so because they express both the CD4 and the CD8 markers of their surface. At this stage, these cells also re-arrange the α-chains of the αβTCR meaning that we are just about to have mature αβTCR T cells that can undergo further differentiation into either single CD4 or CD8 T cells.

All the other markers expressed in the DN stages are not expressed here. Therefore, the DP cells have no c-kit, no CD44, and no CD25 markers. They are only CD4⁺CD8⁺ T cells preparing to commit to single lineage cells.

Mature Single Positive T cells

In this stage of T cell development, thymocytes commit to a single lineage of T cells. They can either become T helper cells meaning that they will express CD4 and completely downregulate the expression of the CD8 co-receptor.

On the other hand, these cells could become cytotoxic T cells meaning that they will express the CD8 co-receptor and downregulate the CD4 in totality. Therefore, at this point, we shall have two subpopulations of T cells that will be trained on antigen recognition. This is what is called positive and negative selection (to be discussed later).

The T cells, after this training, will exit the thymus through the cortex into the peripheral blood circulation. They will leave as naïve CD4 T cells (T-Helper and T regulatory cells) and CD8 T cells (cytotoxic T cells) ready to protect you against foreign antigens.

T cell Receptor (TCR) Development

As already mentioned above the TCR gene re-arrangement process will occur at the DN3 stage for the β-chain genes and at the DP stage for the α-chain genes. The re-arrangement of these two types of chains will yield αβ-TCRs on thymocytes. This is the dominant type of TCR in most T cells (approx. 95%).

However, some T cells will have another type of TCR whose chains are gamma (γ) and delta (δ). This subset of T cells will therefore have γδ-TCRs. It is only a small fraction of T cells (about 5%) that are finally released into the peripheral blood circulation that has this type of receptor. 

Positive and Negative Selection

Although we already mentioned the positive and negative selection, I would like to explain them well here and even use an analogy for you to understand these processes in the best way possible.

Analogy: In my view, these two processes are like a school where the T cells are enrolled, undergo training, and are examined. Those that fail the exam are expelled (die through apoptosis) while those that pass the exam survive to continue with development.

I hope that analogy will make sense to you as I explain the two processes in the next sections. And it should. It is generally agreed that positive selection occurs in the cortex while negative selection occurs in the medulla. These processes happen near the cortico-medullary junction of the thymus.

Positive Selection

In this process, the T cells are trained on how to bind to self-major histocompatibility complex (MHC) molecules expressed by the thymic stromal cells. Those that bind with appropriate affinity are spared to continue with development.

It means that they can bind and strongly recognize foreign antigens presented to them in the context of self-MHC by antigen-presenting cells. Those thymocytes that bind with weak affinities (failed the test) die by apoptosis because they cannot be helpful. This is what is referred to as positive selection.

Negative Selection

Here the cells undergo the test of binding to self-proteins derived from the thymic environment and presented to the T cells by bone marrow-derived macrophages and dendritic cells.

Now, for the T cells to pass the test here, they shouldn’t bind the self-antigens with very strong affinity. If they do, they have failed the test and they die by apoptosis. This is what is called the negative selection of T cells. What binding to self-antigens with strong affinity means is that these T cells will potentially cause autoimmunity (fighting your body cells) in the future.

Autoimmunity is a serious immunopathological problem that has given rise to more than 80 different types of autoimmune diseases in modern times. That is why potentially autoreactive T cell clones must be deleted. There are, however, other mechanisms in the peripheral blood circulation that remove the T cells that may accidentally escape this process of removal.

Conclusion

The process of T cell development is complex but very important in immunology. The importance of T cells in the immune system cannot be overemphasized. T cell development occurs predominantly in the thymus during childhood.

The processes of TCR gene re-arrangement and positive selection give rise to T cells with different TCR repertoires for the diverse range of potential foreign antigens. Negative selection ensures that potentially autoreactive T cells do not sneak into the peripheral blood circulation.

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