T-cells with self-reactive T-cell receptors are eliminated via the process of central and peripheral tolerance. Self-peptides are transported from different tissues in the body to the thymus, where they are presented to T-cells, which then receive pro-apoptotic signals. But how does the body know which peptides are self-peptides? Why aren't e.g. cancer neoantigens presented in the thymus as self-peptides? Is there a temporal component to it?
Hi Martyna, good questions. The immune system doesn't know what peptides are self and which are non-self. Thymic selection can eliminate some self reactive T cells but apparently not all of them. The negative selection process will kill off T cells that bind self really well but the T cells for tissue specific antigens get through. Those have to be controlled by peripheral tolerance mechanisms, the lack of "danger" signals and such. There are some really great papers demonstrating some of this, like transgenic mice that express LCMV in the pancreas and transgenic TCR for LCMV. The T cells are not negatively selected, and the pancreas has no problems until the mice are infected with LCMV. Then the pancreas is wiped out. Or for that matter, normal humans often have T cells that recognize myelin basic protein but only a small percentage of us have MS. A
There are also many papers exploring how the thymus shapes the immune repertoire. My favorite was a pair of papers that created mice that had only one peptide presented by class II. One group deleted the peptide exchange molecule (DM) and the other group (Kappler and Marrack) engineered it so that CLP couldn't be removed from the binding groove. In each case the mice generated an allogeneic response to H-2 matched wt mice because the T cells hadn't been deleted in the thymus.
Dear Martyna,
the self peptides are actually not transported to the thymus, but instead expressed on MTEC cells by a process called "promiscuous expression". T cells with high avidity to all these peptides are removed. However, T cells with low avidity to self-antigens can still pass the thymus, possibly leading to auto-immunity. I recommend the literature from Kyewski et al. for deeper details.
Best wishes
Christoph
Hi Anne and Christoph,
Thank you so much your comments and references to literature, I found it very helpful!!
Kind Regards,
Martyna
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