Human Anatomy, Physiology, and Medicine. Anything human!
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Precursor T-cells undergo positive and negative selection in the thymus. Negative selection eliminates T-cells that bind strongly to self antigens (e.g. produced by the AIRE gene).
However, how is it ensured that only SELF antigens are tested for during negative selection? Perhaps some virus antigen has invaded the thymus and all T-cells that strongly bind with it are also eliminated. This would result in no T-cells being released against that virus, and hence no immunity against it!
How easy is it for a virus to invade the thymus, and how can the purity of self antigens be maintained if it happens - so as to ensure that only self and nothing but self antigens are presented to T-cells during negative selection?
There was an interesting review article in Immunological Research by Edwards & Evavold ("T cell recognition of weak ligands...; 2011"), where they handled the properties of T cells responding to the T cell receptor signals. Although the article focused mainly on autoimmunity, they said that many clonal TCRs can recognize several epitopes with varying affinities - with varying outcomes. So even if a virus could invade the thymus and thus eliminate the T cells specific for it, the somewhat loose nature of TCR binding would allow other T cells with near-identical TCRs to recognize the virus.
Viruses actually generate a lot of "escape mutants", which means that they mutate their T cell epitopes in order to avoid the immune system, but the looseness of the TCR recognition allows the immune system to utilize even some non-specific TCRs to fight the virus. The downside of this is the increased risk of autoimmunity, because these "loose" TCRs may recognize self antigens in a similar manner as they recognize (mutated) viral antigens.
I do not know if some viruses actively seek to invade the thymus and try to present their own antigens as "self", but I guess even if this happened, the overlapping specificities of TCRs should be able to handle the situation.
Interesting... But if this loose nature of TCR binding allows T cell recognition of the virus to a degree that enables it to successfully eliminate the virus from the host, then shouldn't we also expect a large degree of auto-immunity via the same mechanism? If loose binding TCRs are good enough to eliminate/control viruses (even mutating ones) then they should also, with the same vigor, eliminate normal cells coated with self antigens. This should cause considerable (or even fatal) auto-immune effects, but obviously that is not what happens in reality.
Right, and that's the issue I have with this explanation. If it works for viruses, then it should also work for self, and to the same degree of effectiveness. If it's enough to kill viruses, the same mechanism should also kill the host.
If I understood correctly (and one of my own experiments suggests similarly), you should think of the TCR affinity scale as a sort of a slider: in one end you have high-affinity, microbe specific T cells (for example T cells specific for the influenza virus haemagglutinin have typically very high affinity), which are quickly able to initiate an immune response that eliminates the virus. However, these T cells lose their edge easily if the virus mutates. And somewhere in the middle of the scale you have T cells that have "loose" TCRs, which means that they are not very effective in eradicating the virus, but have a better chance to catch the mutant ones as well. However, with bad luck they can also recognize self antigens and initiate a response against own cells. In the other end you have TCRs that are more likely to recognize self antigens than foreign ones, and these are the ones that the body either tries to eliminate in the thymus or tries to turn into regulatory T cells that do not initiate the immune response but suppress it instead.
This is of course a very complex thing as a whole and a lot is still unknown, but it seems that the body favours a repertoire of T cells that are at the or close to the high-affinity end of the scale. That is how it can respond to microbes and other appropriate antigens, still has some "looseness" in the repertoire in case of mutants but not so much as to cause severe autoimmune problems. Many healthy people actually have responses against self antigens, but apparently the regulatory elements of the immune system keep these T cells in check. In addition to autoimmunity, loosely-binding TCRs seem to be associated with allergies as well: people with atopy seem to have more of the low-affinity, allergen-specific T cells than healthy people. The TCR affinity also affects the cytokine production of the T cells, and the loose TCR binding of allergens seems to favour the IgE production of B cells that leads to allergic symptoms.
It has been studied with mice that if you infect normal wild-type mice with the herpes virus, they die of it. If you remove all the regulatory T cells from the mice, they actually kill the virus because the immune system can work without limits and the mice do not die of herpes - but later they develop severe autoimmunity that kills them. So there clearly seems to be a fine balance between the effector and regulatory functions of the immune system: the response must be quick and specific, but not too specific so that it can cover mutants as well, and it must be strong enough to eliminate infections, but not so strong that it severely damages the own system. And the more you have breadth in the TCR binding, the more you risk autoimmunity while covering possible mutant microbes and such.
DISCLAIMER: I'm still trying to figure out this concept myself as well, so the above stuff is what I have gathered so far and should not be taken as a 100% proven truth. I may have misunderstood or forgot something, but I hope I am not too far off from reality with my current view :)
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