T-cell activation

Definitions & Key takeaways

T-cell activation is the process by which an antigen-presenting cell (APC) activates a T-cell. It is an important part of the immune system, as it helps the body to fight off infections and other foreign invaders. During T-cell activation, the APC presents antigen to the T-cell receptor, which then triggers a cascade of signals inside the T-cell, leading to the activation and proliferation of the T-cell. The activation of the T-cell leads to the production of cytokines and other immunological molecules, which help to target and destroy the invading pathogen.

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The adaptive immune response is highly specific for each invader. The cells of the adaptive immune response have receptors that differentiate one pathogen from another by their unique parts called antigens.
The key cells of the adaptive immune response are the lymphocytes, the B and T cells. T cells develop in the thymus where they undergo a process called VDJ rearrangement to generate a massively diverse set of T cell receptors or TCRs.
There are two types of T cells which are identified based on molecules they express on their surface. Helper T cells express CD4 on their surface, and their main function is to support other immune cells.
Cytotoxic T cells express CD8 on their surface, and their main function is to kill infected or cancerous cells. A T cell starts out naive and then gets primed or activated, at which point it differentiates into an affector or memory T cell and proliferates.
Activation of both helper and cytotoxic T cells requires two signals. The first signal occurs when a T cell receptor binds to an antigen, specifically an antigen that's a protein rather than a carbohydrate or lipid.
Now, protein antigens entering the body are first picked up by antigen presenting cells like dendritic cells and taken to the lymphoid organs which are home to the naive T cells.
The antigen presenting cells then process the antigens and display them on molecules present on their surface cell called major histocompatibility complex, also known as MHC.
MHC molecules act like serving platters to present the antigen to T cells. There are two types of MHC molecules that work with the two types of T cells.
MHC class 1 molecules present antigen to CD8 positive T cells, and MHC class 2 molecules present antigen to CD4 positive T cells.
MHC class 2 molecules are found on the surface of an antigen presenting cell like a macrophage or dendritic cells, while MHC class 1 molecules are found on all nucleated cells throughout the body.
The antigen presented on the MHC molecule must be the right size and shape to bind strongly to the T cell receptor or TCR, which is closely associated with the CD3 protein complex on the T cell surface.
The CD3 protein complex consists of six peptide chains, 1 gamma, 1 delta, 2 epsilon, and 2 zeta chains forming 3 dimers gamma, epsilon, delta, epsilon, and zeta zeta.
The TCR itself is composed of an alpha chain and a beta chain, each of which has two domains a variable domain and a constant domain.
The variable regions of the alpha and beta chains of the T cell receptor bind to the antigen presented by the MHC molecule.
Whether it binds MHC1 or MHC2 depends on if the T cell expresses CD4 or CD8. The constant domain has a short transmembrane segment and a short cytoplasmic segment.
The transmembrane segment contains cysteine residues which allow two adjacent chains to form a disulfide bond connecting the chains to one another, and the variable domain of the alpha and beta chain come together to form a single antigen binding site.
This is different from the B cell receptor, which has two antigen binding sites. Also, unlike the B cell receptor, the T cell receptor is surface bound and cannot be secreted.
Now, in addition to the T cell receptor, CD4 binds to the MHC class 2 molecule and CD8 binds to the MHC class 1 molecule, and that helps secure the interaction between the T cell receptor and the MHC molecule.
Second, the cytoplasmic portion of the alpha and beta chains of the T cell receptor are rather short. As a result, the signal that the T cell receptor has successfully bound an antigen gets sent down other portions of the CD3 complex, as well as the CD4 or CD8 molecules.
The 2nd signal required for T cell activation is called co-stimulation. And it's when a ligand that's on the surface of a T cell called CD28 binds to a protein called B7 on the antigen presenting cell.
Antigen presenting cells start expressing higher levels of B7 on their surface, primarily when they encounter foreign antigens and also when they are inflammatory cytokines like interferon gamma, IL-1 beta, and TNF alpha around.
Now if a T cell sees its antigen without co-stimulation, it becomes allergic, meaning that the cell won't get activated even if it sees the antigen in the future.
This extra layer of security prevents T cells from automatically getting turned on, just like how a cell phone needs to get unlocked to make a call.
It prevents mistakes from happening. When a T cell and antigen presenting cell are interacting.
The region where the T cell receptor is bound to MHC antigen. And either CD4 or CD8 and B7 is bound to CD28, is referred to as the immune synapse.
Once the T cell has received both signal 1 and signal 2, it has to send that signal down to the nucleus so that the cell knows it should respond.
This is done using the CD3 peptide chains that have an intracellular component. In all, there are 2 epsilon chains and 2 zeta chains, and one each of the alpha, beta, gamma, and delta chain.
All of these, except for the alpha and beta chains, have at least one immunoreceptor, tyrosine-based activation motif, or IT for short.
The Iam is part of the peptide chain that includes two tyrosine amino acids perfectly spaced out by other amino acids between them.
This is really important because both tyrosines need to be phosphorylated for the cell to get activated. Each gamma and delta have one ITam region.
The two epsilon chains each have one ITA region, and the two zeta chains each have 3 ITam regions, a total of 10 IT regions altogether.
The binding of CD4 or CD8 to the MHC molecule causes the kinase LCK, which is bound to the CD4 or CD8, to phosphorylate all of the items in the CD3 complex.
Once that happens, another tyrosine kinase called zap 70 comes along. Awesome name, right?
Zap 70 binds to the phosphorylated Iams on the zeta chains of the CD3 complex and becomes activated. Activated zap 70 then phosphorylates the linker of activated T cells or LAT, which is a transmembrane protein with a large cytoplasmic tail.
Zap 70 also phosphorylates the protein SLP 76, and LAT and SLP 76 work together to trigger a chain of events that ultimately activates the major transcription factors NF kappa B and NFAT.
These transcription factors increase the expression of cytokines like IL-2, IL-6, and TNF alpha. They also cause upregulation of cell surface markers like BCL-2, which provide a strong survival signal to the T cell so that it proliferates and differentiates.
The activated T cell helper also begins making lots of cytokine IL-2 and up-regulates its IL-2 alpha receptor. The IL-2 receptor has three protein components alpha, beta, and gamma.
A naive T cell only expresses the beta and gamma components of the IL-2 receptor, but these have a low affinity for IL-2, in contrast to the alpha component like the IL-2 receptor, which has high affinity for IL2.
Using the beta and gamma components is like trying to eat an apple with only your lips and tongue, and up regulating the alpha component is like using your teeth to take a big bite out of the juicy apple, much more effective and satisfying.
As a result, active T cells bind to the IL-2 that they make, a form of autocrine stimulation or a cell stimulating itself.
In response to the IL-2, the activated T cell starts to rapidly undergo cell division to form antigen-specific clones, a process called clonal expansion.
If the cell is a CD4 T cell, it will also produce its own IL-2, allowing it to make and eat its own food. CD4 T cells also produce IL-2 for nearby CD8 T cells, which aren't as good as making IL-2.
Activated T cells proliferate and differentiate either into affector T cells, which play a role in fighting infections in certain cancers, or memory T cells which live on long after an infection is eradicated and respond much more aggressively on subsequent exposure to the same antigens.
Now, once the infection is cleared, the immune response contracts, which means that the immune system reverts to its baseline state by withdrawing its warriors, the lymphocytes, from the battlefield.
The primary reason behind the contraction of the T cell response is the elimination of the microbe, and along with it, the stimuli required for lymphocyte survival and activation, the antigen and co-stimulatory signals.
Without the much needed survival signals, the T cells, except memory T cells, undergo apoptosis or programmed cell death.
The entire T cell response fades away within 1 or 2 weeks following the eradication of the infection. Alright, as a quick recap, there are two types of T cells, helper T cells that express CD4 and cytotoxic T cells that express CD8.
To activate a T cell, you need two signals. Signal one is the antigen in the MHC molecule, and signal two is co-stimulation, which is when CD28 on the T cell binds B7 on the antigen presenting cell.
This sets off a cascade of phosphorylation, which ends with the high affinity IL-2 alpha receptor being expressed on the cell surface.
This lets the T cell bind IL2, like sinking teeth into an apple, which causes T cells to proliferate and differentiate into effector and memory T cells.
Once the infection is cleared, the T cell response contracts since the stimulatory signals needed for the survival and activation of the T cells disappear, causing them to undergo apoptosis.