T-cell development
Definitions & Key takeaways
T cells, also known as T lymphocytes are a type of lymphocyte that play a central role in cell-mediated immunity. The process of T-cell development begins with the migration of immature T-cell precursors from the bone marrow to the thymus gland, where they undergo a series of steps to become fully mature T-cells. In the thymus, T-cells are exposed to a diverse array of self-antigens and undergo positive and negative selection to ensure that only T-cells that recognize foreign antigens but not self-antigens are allowed to leave the thymus and enter the bloodstream.
During positive selection, T-cells that recognize self-antigens displayed by thymic stromal cells receive survival signals, allowing them to continue their development. During negative selection, T-cells that recognize self-antigens too strongly undergo apoptosis to prevent the development of autoimmunity. Once T-cells have successfully completed positive and negative selection, they leave the thymus and enter the bloodstream, where they travel to various organs and tissues to carry out their functions.
Your immune system is like the military with two main branches, the innate immune response and the adaptive immune response.
The innate immune response is immediate and nonspecific. Meaning that although it can distinguish an invader from a human cell, it doesn't distinguish one invader from another invader.
In contrast, the adaptive immune response is highly specific for each invader. And that's because the cells of the adaptive immune response have receptors that differentiate one pathogen from another pathogen by their unique parts called antigens.
This adaptive immune response takes days to weeks to become activated. During which time the innate immune system provides the protection.
The second important feature of the adaptive immune response is that it has memory, which means that once a response against an antigen is triggered, subsequent responses will be faster and stronger.
Now, the key cells of the adaptive immune response are the lymphocytes. The B and T cells which are generated during lymphopoiesis lymphopoiesis has two main goals to generate a diverse set of lymphocytes, each with a unique antigen receptor.
And to get rid of lymphocytes that have receptors that are self reactive, meaning that they could attack one's own healthy tissue.
Normally, hematopoietic stem cells within the bone marrow mature into a common lymphoid progenitor cell which then becomes either a B cell or at cell to become a B cell.
It has to develop into an immature B cell in the bone marrow. And then it completes its maturation in the spleen to become at cell.
It has to migrate to the thymus and become a thymocyte where it completes its development into a mature T cell. So B for bone marrow and T for thymus in T cell development, the common lymphoid progenitor leaves the bone marrow and goes to the thymus because that's where the developing T cells or thymocytes mature.
The thymus is a fatty organ that sits in front of the heart. And as we age much like our waistlines, the thymus gets fattier and fattier.
This fat crowds out the space that used to be reserved for T cell development. And it's one reason why cell mediated immunity declines over time.
A process called involution of the thymus. So the thymus has an outer cortex and an inner medulla within the medulla.
There are epithelial cells as well as dendritic cells. Both thymic epithelial cells and dendritic cells present antigens to developing T cells on molecules called major histocompatibility complexes or MHC molecules.
Thymic epithelial cells will also support the developing T cells. Now, antigen presentation is important because T cells have T cell receptors that can only bind peptide antigens if they're displayed on an MHC molecule, which is sort of like a silver platter.
So if the T cell receptor can't bind to the MHC molecule, then the T cell isn't going to be able to do its job. So, of course, a key element of T cell development is formation of this T cell receptor, which is made of two chains, an alpha chain which is like the light chain of A B cell receptor and a beta chain, which is like the heavy chain of A B cell receptor.
The alpha and beta chains are made up of gene segments called V for variable D for diversity. And J for joining the beta chain includes one V segment, one D segment and one J segment.
While the alpha chain only contains one V segment and one J segment. Every person inherits multiple copies of the VD and J segments and they can be rearranged interchangeably to make a unique structure.
This is kind of like how you might have several pairs of shoes, pants and shirts and can mix and match them to create lots of different outfits.
For the alpha chain. Each person has between 7080 variable or V gene segments and 61 joining or J segments.
And that's just for the alpha chain, there are more VD and J segments for the beta chain. So one T cell might have a beta chain on its T cell receptor that has a V 1 D3 J five combination and an alpha chain that is V seven J two.
And another T cell might have a beta chain that has a V 44 D 10 J one combination and an alpha chain that is V two J three.
Thus making completely different T cell receptors with completely different antigen specificities. Now to have a fully functioning T cell receptor at cell has to get through a series of successful gene rearrangements first for the beta chain and then the alpha chain and if the T cell fails at any stage, it dies.
This is a quality control mechanism that ensures that only T cells that express working or functional antigen receptors will make it through the gauntlet of maturation.
T cell development is broken into three key stages based on which key molecules it's expressing on its surface at any given time.
These molecules C D3 CD four and CD eight are expressed. In addition to the T cell receptor, all T cells express the C D3 molecule which is part of the T cell receptor.
And once the T cell is fully mature, it will either express CD four or CD eight. When the common lymphoid progenitor first derives in the thymus, it doesn't express anything on its surface.
So it's considered C D3 negative CD four, negative and CD eight negative. And it's referred to as a double negative stage or DN stage cell because it has neither CD four nor CD eight.
At this point, the DN stage can be further broken down into DN one, DN two, DN three and DN four. As the cell moves through the steps to create a functional T cell receptor, it will then begin to express C D3.
In addition to CD four and CD eight, all on the same cell. The dual expression of CD four and CD eight is why it's called the double positive or DP stage.
Once the cell completes its expression of a functional T cell receptor, it will continue to express C D3, but then it'll downregulate expression of either CD four or CD eight and be known as a single positive T cell or SP.
Throughout all of these stages. The T cell interacts with epithelial cells of the thymus which release growth factors as well as molecules like interleukin seven and two called il seven and il two for short.
And these make the DN one cells mature two enzymes. Rag one and rag two, start getting expressed.
And that signifies that the cell is now ad N two cell. Now these two enzymes work together as a multi subunit enzyme aptly called V DJ recombinase to start forming the beta chain, they rearrange together D and J segments on both chromosomes and the chromosome that successfully rearranges first will then suppress the other chromosome from rearranging a process called allelic exclusion.
This step is important so that each cell expresses only one receptor which can recognize only one antigen. If a cell successfully joins ad segment to AJ segment, then it's considered ad N three cell.
Now, the DN three cell has to attach its DJ gene segment to a V gene segment. Once the V DJ segments are combined, the full beta chains, antigen binding site is complete and gets translated from DNA into messenger RNA.
Then it needs to be recombined with a constant region of the T cell receptor. And eventually this results in a complete receptor protein at this point.
The cell is considered ad N four cell. Finally, it's time to test out if the beta chain is functional by seeing if it can bind to an invariant pre T alpha chain and get expressed on the cell surface.
The invariant pre T alpha chain is basically something for the beta chain to practice with until the real alpha chain is eventually made.
So the beta chain, the invariant pre T alpha chain and C D3 are all expressed on the surface together. The T cr complex sends a signal down the cytoplasmic tails of the receptors to the cell's nucleus.
When the signal is sensed within the cell, the cell starts to divide and the daughter cells of the rapidly proliferating D and four cells are called DP cells because they begin to express both the CD four and CD eight on their surface.
The DP cells now start rearranging the alpha chain, which means that all the DP cells will have the same beta chain, but each will have its own distinct alpha chain.
As long as it creates an alpha chain that can bind to the beta chain and is not self-reactive. The DPT cell moves on to the next step.
If it doesn't, the developing T cell dies, T cells then undergo positive selection, which is another quality control process that makes sure that T cells can recognize and bind to MHC molecules as well as negative selection, meaning they don't bind too strongly to become self-reactive and attack self tissue and cause disease.
Now, the T cell receptor has evolved to recognize both peptides which are part of protein antigens and MHC in positive selection, only the DP cells that bind to an MHC molecule are allowed to survive those that don't are killed off.
Remember that there are many MHC variants in the population and each of us has only one set, but all of us have to generate TCRS that can recognize any.
Because when we are producing the receptors by gene arrangement, the genes don't know which MHC type we have. So there has to be a selection step in which we preserve the cells that can recognize our own MHC, which are the only MHC our T cells will encounter after they are mature.
This step is positive selection. It ensures that of all the immature T cells that develop, which can recognize a variety of MHC molecules.
The ones that go on to mature in each individual can bind only to MHC molecules expressed by that particular individual in negative selection.
It allows these epithelial cells to serve as a microcosm of the entire body. Kind of like how the PCO T Center Theme Park in Florida is a microcosm of the world.
So that allows the body to test out these newly formed T cell receptors in a safe environment. If ADP cell binds strongly to a self antigen, then it dies swiftly and silently by apoptosis.
Whereas if ADP cell recognizes self MHC but does not recognize the self antigen presented in the MHC molecule, it will go on to become a single positive naive T cell by down regulating either the CD four or CD eight receptor.
So the question is, which should it downregulate CD four or CD eight? This is determined by how strongly the T cell receptor binds to the invariant regions of the MHC molecules.
Whenever at cell receptor. And MHC molecule bind CD four binds to the MHC class two molecule a bit like an arm that reaches out and holds the T cell receptor and MHC together.
So if there's ADP cell, its CD four will bind to an MHC two molecule. Now, if the strength of the binding between the T cell receptor and the MHC class two molecule is somewhat strong, then the cell will downregulate CD eight and become a single positive CD four positive T cell.
On the other hand, if the strength of the binding between the T cell receptor and the MHC class two is somewhat weak, then the cell will downregulate CD four and become a single positive CD eight positive T cell.
At this point. The cell is considered a single positive naive T cell that will travel to the secondary lymphoid organs like the lymph nodes or the spleen to deal with antigens presented on MHC molecules by antigen presenting cells like dendritic cells as a quick recap T cell development occurs in the thymus and has a few key tasks, rearrange the beta chain, rearrange the alpha chain, make sure that T cells bind the MHC molecule called positive selection.
And that the T cells aren't self-reactive called negative selection. The beta chains first combined DJ segments, then the V DJ segment forms and finally, a constant region is added on a complex forms with the beta chain, the invariant pre T alpha chain and the C D3 molecules.
At that point, the cells proliferate and each daughter cell rearranges its alpha chain, combining a V segment to AJ segment.
The alpha chain will then join the beta chain and undergo positive selection and negative selection to make sure that the TCRS can bind MHC molecules but are not self reactive.
At this point. It becomes either a naive CD four positive T cell or a naive CD eight positive T cell and is released into the periphery.
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