Innate-like T cells
Learn more about the unique properties of innate-like T cells and why they are interesting as therapeutic targets.
Most T cells start out as inexperienced cells, called naïve cells, that do not possess yet any effector functions needed e.g. to fight pathogens. They can gain such functions only after a lengthy stimulation and differentiation phase. The stimulation is dependent on the interaction of the cell’s unique antigen receptor, called T cell receptor (TCR), with a protein fragment (the peptide antigen) that binds to an antigen-presenting molecule (called MHC) specialized in presenting such peptides. T cells with these features are called conventional T cells.
The power of these conventional T cells relies on the fact that almost every T cell in the human body expresses one unique TCR. These billions of TCRs combined with a high variability of MHC molecules, which each can bind thousands of different peptides, almost guarantees that for every protein entering the body, e.g. as part of a virus, there could be T cells that get activated and could enter the fight.
However, about 15-20% of the T cells found in the human blood differ significantly from these conventional T cells and are called collectively unconventional T cells. Unconventional T cells are characterized and distinguished from conventional T cells by three key features:
(i) Their TCR displays limited diversity, meaning many unconventional T cells use the same TCR.
(ii) Their TCR does not recognize peptides or peptide-binding MHC molecules.
(iii) Unconventional T cells develop as fully functional memory cells and can display pronounced effector functions within an hour of activation. This rapid activation is more reminiscent of innate immune cells, which explains their alternative name as innate-like T cells.
Due to this ability to rapidly display strong effector functions, innate-like T cells have a pronounced effect on the immune system and provide a first line of response against, for example, infections.
Although many subtypes of unconventional or innate-like T cells exist, the three best-understood ones are iNKT cells, MAIT cells, and γδ T cells.
​
1) Invariant Natural Killer T (iNKT) cells: Human iNKT cells are characterized by the expression of an invariant TCR α-chain, Vα24-Jα18, which is shared by all humans. This TCR recognizes glycolipids presented to them by the monomorphic MHC molecules CD1d. These glycolipids can be derived from bacteria, fungi, or host cells.
​
2) Mucosal-associated invariant T (MAIT) cells: The TCR of human MAIT cells uses an invariant TCR α-chain, Vα7.2-Jα33, to recognize riboflavin derivatives in the context of the monomorphic MHC molecules MR1. These riboflavin derivatives are produced by some bacteria.
​
3) γδ T cells: In contrast to all T cells mentioned here, whose TCR consist of one α- and β-chain, the TCR of γδ T cells consist of one γ- and one δ-chain. This γδTCR does not need to interact with antigen-presenting molecules, as it can directly bind to foreign or self-antigens.
Relevance and impact
​
Due to their potent innate-like features, iNKT, MAIT, and γδ T cells are important players in the early phase of many diseases, making them interesting targets for novel therapies.
​
Furthermore, conventional T cells have several drawbacks that complicate their use for cell therapy. Most of these drawbacks are irrelevant for innate-like T cells, making them potentially more versatile than conventional T cells for cellular immunotherapies.
​
Meriel Biosciences is dedicated to making these promises a reality.
​