Cell-Mediated Immunity I

In my last post, I talked about humoral activity, which is mainly to do with antibodies as well as the cells that produce them (B-cells). In this post, I'm going to talk about cell-mediated immunity, which has to do more with T-cells, as well as with some other cells like NK cells and macrophages.

Describe T-cell types and functions

Firstly, we're going to talk about T-cells! I've talked about the broad categories (cytotoxic, helper and regulatory/suppressor) before, but now I'm going to provide a little bit more detail.

• Cytotoxic T-cells: Express CD8. Go around killing virus-infected cells.
• Helper T-cells: Express CD4. Release signalling molecules such as cytokines which helps to coordinate the immune response (for example, in my last post I mentioned how cytokines from helper T-cells can cause B-cell activation).
• T_H1 cells: Activate infected macrophages.
• T_H2 cells: Provide help to B-cells for antibody production
• T_H17 cells: Enhance the neutrophil response and promote barrier integrity of the skin, intestines etc. Critical in inflammatory responses. Implicated in autoimmune diseases.
• T_FH cells: The "FH" stands for "follicular helper," as they are generally located in follicles. Help out B-cells in process such as isotype switching (class switching).
• Regulatory T-cells: Express CD4. Suppress T-cell responses.

Different types of cells can target different types of pathogens. For example, cytotoxic cells tend to target pathogens that replicate in the cytosol, such as viruses and certain bacteria such as listeria. T_H1 cells, on the other hand, target pathogens that can survive macrophage vesicles, such as mycobacteria and leishmania.

Describe T-cell activation
Describe APC-T cell interactions
Describe T-cell effector mechanisms

To describe T-cell activation, we have to go back a bit and talk a tiny bit about APCs (antigen-presenting cells). As should be burned in your memory by now, T-cells need to see an antigen presented on the surface of an APC before it does anything. Hence, perhaps you could say that the very very first step in T-cell activation is antigen uptake by an antigen-presenting cell, such as by a Langerhans cell underneath the skin (which is where a pathogen would get in if you had a cut). The antigen-presenting cell then makes its way to the lymph nodes.

Let's keep going on with this example using Langherhans cells. Just to refresh your memory- Langerhans cells are dendritic cells found just under the skin. Those that haven't seen their antigen yet are considered immature. Once they find their antigen and move to the lymph nodes, they mature and can even transfer some antigens to other dendritic cells in the lymph nodes. They can also stimulate naïve T-cells.

As mentioned in a previous post, the main signals in T-cell activation are binding to the peptide/MHC complex, B7 on the APC binding to CD28 on the T-cell, and cytokine binding. Fun fact about B7: it can be prevented from binding to CD28 by binding to another molecule on the T-cell surface called CTLA-4. CTLA-4 binding delivers inhibitory signals, shutting off the immune response, which is good when it happens at the end of an immune response as it normally does. Some tumours, however, might have high amounts of CTLA-4, blocking the immune response and therefore stopping the tumour from being killed by the immune system.

Just like with B-cells, the types of cytokines used for signalling can determine the differentiation pathway of the T-cell:

IL-12/IFNγ -> STAT4 -> T_H1
IL-4 -> STAT6 -> T_H2

Also, a transcription factor called FoxP3 is implicated in differentiation to T_reg cells. However, we don't need to know what cytokines activate FoxP3 for now.

On the topic of cytokines, it's a good idea to also learn what types of cytokines are secreted by the different cells. So here's a (very brief) list:

• T_H1 secretes IL-2 and IFNγ
• T_H2 secretes IL-4 and IL-5, which are also critical in allergic responses
• T_H17 secretes IL-17
• T_reg secretes TGF-β and IL-10, which are anti-inflammatory cytokines

Activation of cytotoxic T-cells

Okay, back on track. Let's have a look at how helper T-cells and cytotoxic T-cells can affect each other with the help of a pAPC (professional antigen-presenting cell).

First of all, a T-helper cell interacts with an antigen-presenting cell via CD40L (on the T-helper cell) binding to CD40 (on the antigen-presenting cell). This stimulates production of IL-2 from the T-helper cells, as well as 4-1BBL (a cell-surface molecule) on the pAPC. IL-2 can bind to IL-2 receptors on the cytotoxic T-cell, while 4-1BBL can bind to 4-1BB receptors. A combination of 4-1BB, the peptide bound to MHC and IL-2 leads to efficient activation of cytotoxic T-cells.

Let's have another look at the IL-2 receptor, because IL-2 is cool. On naïve cytotoxic T-cells, the IL-2 receptors only have two domains: β and γ. Once the T-cell is activated, it begins to synthesise the α-chain, which is also known as CD25 (you may recall that I mentioned that CD25 was a part of IL-2). When all three chains are there, the receptor binds IL-2 with high affinity.

Death by cytotoxic T-cell

Now let's look at how cytotoxic T-cells can kill stuff by themselves! The first step is for the cytotoxic T-cell to get in all nice and cosy with the cell that they're about to kill. (Kinda ominous, isn't it?) They do this through non-specific adhesion molecules. LFA-1 on the surface of the T-cell can bind to ICAM on the victim, er, target cell. The T-cell can then bind to the peptide/MHC complex. As I mentioned in my last post, the MTOC and other cytoskeletal and cytoplasmic components line up in order to allow the T-cell to "take aim" before releasing effector molecules.

One important type of effector molecule is perforin. It forms pores in the cell membrane of the target cell. As well as potentially causing lysis, these pores also allow the entry of other effector molecules, such as granzymes. Granzymes are serine esterases that can kickstart the apoptosis (cell death) chain.

People who have perforin mutations can still kill other cells, just not as effectively. This is because there are other pathways through which cells can be killed, including FasL/Fas mediated apoptosis. (FasL is a ligand on the cytotoxic T-cell, whereas Fas is a receptor on the target cell.)

And that's it from this lecture! Stay tuned for part 2!