T cells - sentinels of immune recognition

The human immune system recognizes self and foreign molecules with the help of T cells. Every T cell is specific for a given molecular motif. In principle, T cells can form against any molecular motif.

However, it would be especially uneconomical to maintain T cells of any specificity (our body would produce T cells, which are specific for motifs not even found in nature).

T cells survive if they are at least somewhat specific for human molecular motifs

During foetal development, T cell precursors are filtered in the thymus. In this process, the immune system uses motifs of our own body as samples. Only those T cells survive that are able to recognise these motifs to some extent, while others die.

A blind spot for overly dissimilar molecules

It is a widespread opinion in immunology that the more dissimilar a molecule to human ones, the more likely it is recognised by the immune system. Interestingly, the findings of researchers in Szeged, Hungary did not support this interpretation.

They found that the immune system is unable to recognise overly dissimilar molecules to human ones, which can be explained by the mechanism of T cell selection in the thymus: only those T cells survive that can bind human molecules. Pathogens carry many of such molecules, which potentially help them to hide from the immune system.

The researchers showed that the proposed theory could explain the susceptibility to certain infections. Also, the variable response to vaccines could be partially explained by this mechanism, which is currently under investigation by the researchers.

They further speculate that the findings might be applicable to anti-cancer immunity, immunotherapy and tumour vaccination strategies:

"While our results indicate the importance of this blind spot in the immune response to infections, it is a question to be clarified in future works, whether mutated cancer peptides can also reach this level of dissimilarity. Similarly, testing our hypothesis on HLA-II presented peptides and CD4+ T cells is also an important area of future research."

Article: Balázs Koncz, Gergő M. Balogh, Benjamin T. Papp, Leó Asztalos, Lajos Kemény, Máté Manczinger: Self-mediated positive selection of T cells sets an obstacle to the recognition of nonself. PNAS (2021).