T-cell Receptor: Maturation

At the very end of my last post, I said that thymocyte development would be the topic of a later post. Well, this is the later post!

Describe T-cell maturation in the thymus

Firstly, a quick note about the thymus, just in case you don't know what it is. It's a primary lymphoid organ where T-cells are produced, and is located in the anterior mediastinum. As you get older, the thymus shrinks and thus produces fewer T-cells.

Just as with pretty much all aspects of the immune system, the importance of the thymus is highlighted in people who don't have one. People with DiGeorge's syndrome, and Nude mice (mice with a genetic mutation causing an absence of a thymus), lack T-cells and have reduced B-cell activation (as they are no longer receiving signals from T-helper cells). As an aside, there are also Scid mice ("Scid" stands for "severe combined immune deficiency") that lack RAG-1 enzymes, and thus don't have TCRs or BCRs.

Back to the thymus: like many other organs of the body, it has a cortex (outer bit) and a medulla (inner bit). Early thymocytes first enter through blood vessels of the medulla. As they mature, they move up through the cortex, and eventually back down and out through either veins or lymph vessels. Along the way they come into contact with cells such as medullary epithelial cells, cortical epithelial cells, Hassall's corpuscles, dendritic cells and macrophages. The first two types will be important in positive and negative selection, as you will see later. Hassall's corpuscles have an unknown function. As for the last two, hopefully you know what they are by now- if not, have a look through some of my earlier Immunology posts.

An important protein present on medullary epithelial cells is AIRE. AIRE stands for "AutoImmune REgulator." It induces the expression of many different proteins, including those specific for other tissues of the body. This allows the developing thymocyte to be able to meet some of those antigens before even leaving the thymus. If AIRE is defective, there's a much higher risk of immune destruction of other tissues, notably endocrine tissues. This causes a condition called Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy, which conveniently goes by the acronym APECED so we don't have to waste our breath on that long name. Interestingly enough, Hassall's corpuscles appear to differentiate from cells that have lost their ability to express AIRE.

Now onto a bit about the development of the thymocytes themselves! Precursor cells are originally formed in the bone marrow, but then migrate to the thymus. TCR recombination then occurs, yielding either an αβ or a γδ cell. γδ cells can then move out straight away- as they don't recognise MHC molecules, there's no risk of them self-reacting, so there's no need for them to go through all of the processes to weed out self-reactive molecules. αβ cells, however, do need to stick around to continue developing and go through the selection process.

Another type of thymocyte that may be formed is the NK T-cell, which has some properties of T-cells and some of NK cells. Specifically, they express CD3, just like T-cells, and CD56 (a glycoprotein important for adhesion), just like NK cells. Their TCRs have an invariant α-chain and are able to interact with non-polymorphic CD1 molecules, which present lipid antigens. NK T-cells are pretty rare and only make up around 0.1% of peripheral blood T-cells, but their levels may be elevated in some autoimmune diseases as well as in cancers.

Describe developmental stages of T-cells in the thymus with regard to positive and negative selection

Positive selection refers to the signals that cause either a CD4 or a CD8 T-cell to develop, whereas negative selection refers to the removal of self-reactive T-cells. Aside from these processes, many cells die of neglect- there simply aren't enough survival signals to go around. It seems like a bit of a waste, but whatever.

As I mentioned earlier, epithelial cells in the cortex and medulla of the thymus are important in these processes. They express high levels of MHC-I and MHC-II bound to a range of different self-peptides, which basically sets up a test for double-positive T-cells. If the T-cells can't bind at all, they die of neglect. If they bind too strongly, they are given strong signals to undergo apoptosis (negative selection). If they bind "just right," then they are given signals to proceed to the single-positive stage of development (positive selection). Kinda like Goldilocks in a way- you don't want binding to be too strong or too weak, but "just right." Whether a cell becomes CD4+ or CD8+ depends on whether the double-positive T-cell binds to MHC-I or MHC-II: those that bind to MHC-I become CD8+ and those that bind to MHC-II become CD4+.

Negative selection is very helpful in reducing numbers of self-reactive T-cells. It is not perfect, however, because not all tissue antigens are expressed in the thymus. Thankfully there is also a mechanism called peripheral tolerance, allowing auto-reactive T-cells to become inactivated in the periphery. (Negative selection taking place in the thymus is known as "central tolerance.")

And that's it for T-cell development! Next up I'll talk about T-cell activation, which is a wild ride of signalling pathways. Hold onto your hat!