Content Reviewers:Rishi Desai, MD, MPH
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 non-specific, 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 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 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. This, of course, is why vaccines are so effective – once you get a vaccine containing a part of a pathogen, the next time you see that same pathogen, you will remember the previous encounter (from the vaccine) and you will kill it.
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 a T cell. To become a B cell, it has to develop into an immature B-cell in the bone marrow and then complete its maturation in the spleen. To become a T 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 get 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 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 1 V segment, 1 D segment, and 1 J segment; while the alpha chain only contains 1 V segment and 1 J segment. Every person inherits multiple copies of the V, D, 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 70-80 variable (or V) gene segments and 61 joining J (or J) segments, and that’s just for the alpha chain! There are more V, D, and J segments for the beta chain. So one T cell might have a beta chain on its T cell receptor that has a V1-D3-J5 combination and an alpha chain that is V7-J2, and another T cell might have a beta chain that has a V44-D10-J1 combination and an alpha chain that is V2-J3, thus making completely different T cell receptors with completely different antigen specificities.
Now, to have a fully functioning T cell receptor, a T 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 is expressing on its surface at any given time. These molecules, CD3, CD4, and CD8 are expressed in addition to the T cell receptor. All T cells express the CD3 molecule, which is part of the T cell receptor, and once the T cell is fully mature it will either express CD4 or CD8. When the common lymphoid progenitor first arrives in the thymus, it doesn’t express anything on its surface, so it’s considered CD3-, CD4-, and CD8- and is referred to as a double negative stage or DN stage cell because it has neither CD4 nor CD8 at this point. The DN stage can be further broken down into DN1, DN2, DN3, DN4. As the cell moves through the steps to create a functional T cell receptor it will then begin to express CD3 in addition to CD4 and CD8, all on the same cell. The dual expression of CD4 and CD8 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 CD3 but then it’ll downregulate expression of either CD4 or CD8 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 7 and 2, called IL-7 and IL-2 for short, and these make the DN1 cells mature. Two enzymes, Rag-1 and Rag-2, start getting expressed, and that signifies that the cell is now a DN2 cell. Now, these two enzymes work together as a multi-subunit enzyme aptly called V(D)J 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 a D segment to a J segment, then it’s considered a DN3 cell. Now, the DN3 cell has to attach its D-J gene segment to a V gene segment. Once the VDJ segments are combined, the full beta chain’s antigen binding site is complete and gets translated from DNA into messenger RNA. Then, it needs to be recombined with the constant region of the T cell receptor, and eventually this results in a complete receptor protein. At this point, the cell is considered a DN4 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 CD3 are all expressed on the surface together. The TCR 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 DN4 cells are called DP cells, because they begin to express both CD4 and CD8 on their surface.