Imagine you are part of a specialised MI5 task force, aiming to find and neutralise an organised criminal gang. During your investigation you may encounter other criminals, but you are searching for a specific target. In the body, T cells are your agents—they are tasked with the job of finding an invader and migrate around your body in search of pathogens, such as bacteria and viruses. Much like a specialised force, T cells are fussy, with each individual T cell only focussed on targeting a specific pathogen that has infected your body’s cells and is making you sick. Though you may not realise it because you are busy feeling sorry for yourself, curled up on the sofa drinking Lemsip, T cells are working at the molecular level to clear the infection.
In the body, T cells are your agents—they are tasked with the job of finding an invader and migrate around your body in search of pathogens, such as bacteria and viruses
The T cell receptor (TCR) is a uniquely shaped protein expressed on the T cell surface. Through this receptor, T cells recognise small pieces of pathogen-derived proteins, known as antigens. For killer T cells (a subset of T cells) to carry out their job, they first must be “licensed to kill” by interacting with a dendritic cell, a specialised antigen presenting cell which provides them with the biological signals they need to find their target antigen. When the killer T cells find their matching antigen, they produce toxic proteins that kill the infected cell, thus helping to clear up your infection.
As we progress through life, we encounter a wide variety of pathogens. Luckily our T cells all express slightly different TCRs allowing us to fight off an onslaught of invaders. But how do we obtain such a diverse range of TCRs?
Development of TCR Diversity
During development in the thymus, T cells undergo genetic recombination (enzymes connecting gene segments from different parts of the genome) in which the seven gene segments that determine the exact shape of their TCR are selected from a pool of over 100. Before leaving the thymus, the T cells undergo rounds of selection in which their newly formed TCR is tested. During these rounds of selection T cells bearing receptors specific for self-proteins are selected against, preventing the development of autoimmunity.
For many years, this process of T cell development was widely accepted by scientists. Reality, however, turned out to be a bit more complicated.
The mathematics alone were enough to cause some head scratching. If each T cell had one type of TCR that recognises one specific antigen from one pathogen, we would need to have enough T cells to provide protection against more than 1015 unique antigens from various pathogens. This many T cells would weigh more than 500kg, yet most humans weigh considerably less. Thus, the hypothesis of each T cell only recognising an individual antigen is numerically impossible.
It is now commonly accepted that TCRs are cross-reactive—this means that they each recognise two or more (likely many) antigens. Although this cross-reactivity does not pose an issue (and in fact may be beneficial) for the recognition of pathogens, it can become problematic when TCRs are able to recognise antigens naturally expressed in our body. This phenomenon is known as molecular mimicry and can contribute to our immune system treating ordinary tissues in our body as though they are a pathogen.
This case of mistaken identity, much like an MI5 task force identifying and arresting the wrong suspect, is known as autoimmunity. If this immune response is prolonged it can result in damage to the body’s tissues and chronic inflammation leading to autoimmune diseases such as type I diabetes, lupus and multiple sclerosis (MS).
This case of mistaken identity, much like an MI5 task force identifying and arresting the wrong suspect, is known as autoimmunity
Molecular Mimicry in MS
One of the most well-researched examples of molecular mimicry is in MS which is a neurogenerative disease of the central nervous system (CNS) that causes vision loss and motor movement issues. In the 1990s, evidence arose that cross-reactive TCR may contribute to MS. T cells isolated from MS patients were found to be self-reactive to CNS antigens, however, early in life these cells were kept at bay due to their low numbers and the blood-brain-barrier preventing these T cells exerting autoimmune activity. However, should these T cells become activated, they can cross this barrier. It was found that these T cells from MS patients were cross-reactive with antigens on Epstein-Barr virus (EBV), a human herpes virus that establishes persistent infection in 90% of people (although most will never know they are infected with it). This data has been recapitulated in several further studies. If T cells that are self-reactive to CNS antigens become activated by alternative antigens, they may cross the blood-brain-barrier and attack healthy tissue.
Although the T cells responsible for this autoimmune response are present in the body prior to EBV infection, during the infection they divide and proliferate, increasing their numbers. A higher number of T cells expressing the cross-reactive TCR means they are more likely to encounter the antigens in the CNS as they circulate around the body. Additionally, activation by EBV infection makes their threshold for subsequent activation by their antigens lower, so they are more likely to react to the self-antigens in the nervous system.
There are, however, many unanswered questions regarding molecular mimicry and autoimmune diseases. For example, if molecular mimicry can trigger an autoimmune disease, then why does every person who gets infected by EBV not go on to develop MS? The differences between people that develop autoimmunity and those who do not are not fully understood, but underlying genetics and environmental factors likely play a role.
Molecular Mimicry in TCR Engineering
Molecular mimicry needs to be considered when creating treatments for diseases too. The ability to engineer TCRs allows scientists to treat cancer by designing TCRs that recognise antigens expressed by cancer cells. Theoretically, this is an excellent way to treat cancer and has the potential to revolutionise cancer therapy. However, due to molecular mimicry, great care needs to be taken when engineering these TCRs.
The importance of this was demonstrated in a clinical trial in the early 2010s in which two patients were given T cells expressing a TCR that had been designed to recognise a cancer antigen, known as MAGE-A3. Although the TCR had been rigorously tested in the preclinical stage, the two patients injected with the T cells died from fatal cardiotoxicity. It was discovered that the TCR was cross-reactive for a self-antigen (titin) expressed on contracting heart muscle, and the T cells reacting to this protein caused severe damage to the heart.
Research is still needed to fully understand what makes T cells cross-reactive to antigens from seemingly unrelated origins and to enable us to be able to safely use engineered TCRs without fear of fatal cross-reactivity. Scientists around the world are using a variety of approaches, from computational to experimental, to attempt to answer these remaining questions. As TCRs that cross-react to over ten different antigens have been identified, clearly T cells are not as fussy as we once thought they were.