T-Cell Receptors, Part One: The Immtroduction

Part 0: The introduction to the introduction

For those that might not have much background immunology knowledge, here's a quick whistlestop tour of the relevant basics, in order to better appreciate the rest of the series. If you already have a decent immunology or TCR background, you might just want to skip to the next instalment.

Our immune system exists to keep foreign pathogens (viruses, bacteria, fungi, worms, amoebi and so on) out of our body, or under control, to stop them causing us disease.

It works on a simple basis; discriminate between 'self' and 'non-self' (or 'host' vs. 'pathogen', 'us' vs. 'them', 'cops' vs. 'robbers' etc.). The immune system itself can then be divided into two broad categories; innate and adaptive.

Innate immunity is a fast acting defence that's hard-coded in our DNA, protecting us from anything that looks like it might be bad. There are specialised immune cells which are always on the lookout for the usual suspects that we know (from evolutionary experience) would like to infect us. In addition to these special cells, all the other cells in the body contains a number of factors to prevent infection, or to alert the immune system to get them to take care of things.

Adaptive immunity (the focus of this series) is a bit slower, but has the advantage of being, well, adaptable. It's not just about reacting to things, but about trying to antipate what we might be infected with, and remembering what has infected us in the past. Instead of inheriting our adaptive immune systems along with our innate systems, we just inherit the tools to make ours up as we go along.

There are two main white blood cell types responsible for adaptive immunity - T-cells and B-cells - which do different roles, working together to keep invaders out. Due to the nature of how I spent my childhood, I tend to describe them with a gaming analogy; B-cells are your ranged attackers, lurking in the lymph nodes attacking pathogens from afar, while T-cells are your melee troops, patrolling the tissues, looking for any cell that's showing signs of disease.

Both cell types use a very special kind of receptor to look for signs of infection or disease, but do different things once they've found one. An important thing to appreciate though is that all the different T- and B-cells are looking for different signs of infection.

In this series I'm not going to go into exactly how they stop pathogens, focusing instead on how they find them.

Briefly, B-cells secrete antibodies (or immunoglobulins), which circulate through the body and bind specifically to non-self things, such as viruses and bacteria. Binding of antibodies to a pathogen can either directly neutralise them, or can act as a flag to other immune cells, as if to say "hey guys, we found this critter trying to creep in, let's get him!".

T-cells come in more flavours, each with slightly different modes of action, but all work by getting up close and personal with the cells they're surveying. The action of T-cells relies on the fact that all cells in the body display bits of whatever's going on inside of them on their cell surface.

The most important system by which cells reveal what's going inside is the MHC presentation pathway. In this system, cells chop up proteins inside of them, and put the resulting peptide fragments into a special groove in an MHC molecule, before putting the whole thing on the outside of their membrane.

This means that passing T-cells just have to check out the MHCs of a given cell to find out what's going on under the surface, and thus tell if cells are infected (by looking for the presence of non-self peptides on the other cells' MHCs). If it finds a sick cell, a T-cell can either kill that cell directly, or get other cells (including B-cells) involved to sort out the problem.

MHC presentation is so important, there is a cell called the dendritic cell whose main job is to take in antigens from its surroundings, just to display their peptides to T-cells. There are a few other cells who do this, particularly macrophages and B-cells; together they're known as professional antigen presenting cells (or pAPC).

It's a pretty well-oiled machine, with (loosely) B-cells taking care of bad stuff floating around outside of our cells, and T-cells taking care of bad stuff floating around inside of our cells (or just bad cells themselves, like cancer cells).

But how do T- and B-cells recognise these sick cells? The trick is that they make use of very special proteins, called variable antigen receptors (where an antigen is the part of a pathogen or molecule recognised by the adaptive immune system).

The basic principle of these variable antigen receptors is simple, and is based upon the fact that there are more pathogens out there than we could easily encode a response to in our genome.

To explain that a little clearer: there are very many bugs and nasty pathogens out there that would like to infect us. We don't necessarily want them infecting us, so we need ways of detecting (and eliminating) them.

Theoretically we could just lots of genes in our genomes, each encoding a receptor for every different antigen. Sadly, as there are effectively near-infinite potential pathogens, this wouldn't work (as we can't produce a near-infinite genome, due to the lack of nearly-infinitely sized cells).

Instead, we've evolved a fiendishly clever system that uses a relatively small of amount of DNA (a fraction of our genome) to create thousands of times more genes then the rest of our genome could hope to hold. These genes encode the T-cell receptor (TCR) and B-cell receptor (BCR) (whose secreted, soluble forms are antibodies). I'll let you guess which is on which cell type.

Effectively, every different T- or B-cell has a different TCR or BCR, allowing each to recognise a different antigen. Our bodies can make millions (if not gazillions) of TCRs and BCRs, thus enabling us to protect ourselves against a world full of untold nasties.

The antigen receptors are surface expressed heterodimers; that is, they're made up of two different polypeptide chains linked together, and appear on the outside of their respective cells. There are two kinds of TCR, made up of different polypeptides: αβ and γδ TCRs, which are found on the two main different kinds of T-cell (αβ T-cells and γδ T-cells respectively; see, sometimes scientists make nice nomenclature).

Each chain of each receptor is encoded at a different location in the genome (with one noteable exception, that will be discussed in a later blogpost).

At each location, instead of just having one standard, continuous gene (ignoring introns), the DNA that codes for the antigen receptors is instead broken up into an arrays of gene segments, which can be joined in different combinations to produce different proteins, from the same original germline DNA.

These gene segments can be divided up into one of three types: Variable (V), Diversity (D) and Joining (J) regions, hence the name this process is given: V(D)J recombination. In order to bring 'selected' gene regions together, the RAG recombinase complex loops out the DNA between two gene segments and chops the loop out, joining the two cut ends together.

Every receptor chain has a V and a J region, while within a given receptor only one of the two chains contains a D region. In the case of TCRs, it is the β and δ chains that have a D, while the α and γ chains go without.

So, in α and γ chains one of the Js is joined to one of the Vs, while in β and δ there's an extra step; a J must first recombine with a D, then this DJ can join to a V. Recombined variable regions are then spliced onto a constant region in the mRNA, before translation and dimerisation with their partner chain. The region of the protein formed at the intersection between the V(D)J regions is known as the CDR3 region, and is the major factor in determining what antigen is recognised by that TCR.

There are a lot of Vs and Js to choose from (along with a couple of Ds in the chains that have them); you can see how many over at IMGT (here are the α/δ, β and γ loci). This means there's a lot of potential combinations, meaning a lot of different possible TCR. This is aided by the fact that the receptors are heterodimers, so the diversity is compounded.

However, the number of possible TCRs gets really ridiculous when you consider a further two mechanisms used to generate diversity.

When the DNA gets cut in order to be recombined, it's not always entirely accurate; there can be a bit of exonucleolytic 'nibbling' away of the ends. After the nibbling, a different amount of any of the four bases (A, C, T or G) may be added by the enzyme Tdt, before the segments are finally sealed together by DNA repair enzymes.

It might sound fiddly, but it really is a beautifully elegant system for keeping us going in the face of a dangerous microbial world. We can see how important adaptive immunity is when looking at the severe problems faced by people who have a defect in a vital component of the system.

I've only covered a few things here, and even then in a fraction of detail they deserve. I've not even touched on a lot of other hugely important aspects of immunology, such as, I don't know, the role that all the other immune cells play. Even on topic, I've only gone over the bare minimum; maybe in a future series (or later in this one if I have time) I'll cover topics such as how we ensure our TCRs onlyrecognise 'bad' peptide-MHC complexes, or why we need both αβ andγδ T-cells.

For now, this little introduction should be enough to understand most of what I'll be covering in the rest of the series.

On to Part 2: A history of TCR discovery