User:Martin Mihula/MR1-restricted T cell

There are two T-cell subsets recognizing MR1 molecule: MAIT and autoreactive MR1T cells.  MAIT cells are characterized by these properties: they express semi-invariant TCRs encoded by a TRAV1.2 TRAJ33/12/20 gene rearrangement; they can be stained by MR1-5-OP-RU tetramers; they express CD161, CD26 and CD218a markers; they express PLZF transcription factor; and they recognize and are activated by riboflavin metabolites. MR1T cells are heterogeneous population and do not exhibit all these features, most common they don’t express classical TRAV1-2 TCRs[ZZ1] . MR1T cells vary in expression of transcription factors, tissue distribution, function as well as in TCR repertoire and antigen specificity.^[1]

MR1T cells do not recognize microbial antigens, especially compounds of riboflavin pathway, or folate derivatives, such as MAIT cells. Instead, they recognize endogenous antigens and thus can react to tumor-associated antigens (TAA). Cancer cells express MR1 on the surface in constant low levels and that is the reason why MR1T cells do not react to healthy cells ^[2], even they are presented in the blood of healthy individuals with a frequency between 1-2 in 5,000 of circulating T cells.^[3] Because of their ability to recognize TAA, [ZZ1] they are considered as a promising tool in cancer immunotherapy.^[4] Nevertheless, particular target antigens of these cells are still unknown. It is considered that antigens are: various, because different cells react to different fractions; stable within cell lysates; and conserved in mammalians.^[2] In vitro experiment showed that MR1T cells were able to recognize very low numbers of MR1 on the surface of cancer cells. They recognized various types of cancer cells and did not respond to healthy cells. Thus, it is considered that the target ligand is associated with cancer cells survival.^[5]

MR1T express polyclonal repertoire of either TCRαβ or, with significantly less frequency, TCRγδ.^[1] They can produce either Th1 (TNF-α, TNF-β, IL-2), Th2 (IL-4, IL-5, IL-10, IL-13) or Th17 (IL-17, GM-CSF)cytokines and transcriptional factors after ligand recognition. The recognition is mediated by TCR and MR1 with bounded ligand.^[4] Several of these cells can also express NK activatory and inhibitory receptors as well as immune-checkpoint receptors. Some of them can secret large amounts of PDGFα and VEGF.^[1] These molecules support vasculogenesis, angiogenesis and proliferation of mesenchymal cells.^[6] MR1T are either CD8+ or double-negative and some cells can express CD161. They have tissue-homing capacity, however, their expression of CCR4 and CCR6 is low, as compared to MAIT cells.^[3]

Some MR1T cells are activated by non-riboflavin-related molecules and can react against infected cells in Th1-like manner. Specifically, they can react against Streptococcus pyogenes infection. Moreover, they are able to recognize ligands derived from Escherichia coli and Mycobacterium smegmatis. Thus, these cells may participate in antimicrobial immunity.^[7] Other MR1T cells recognized in vitro differentiated monocyte-derived dendritic cells (DCs) and they promoted their maturation. It suggests these cells may be able to modulate DC functions. Other cells responded to epithelial cell lines by releasing of cytokines, such as IFN-γ, IL-8 and IL-13. That promoted expression of mucin, MR1T cells thus probably can be involved in epithelial cell function including promotion of innate defense.^[8]

The MHC-I-related molecule MR1 is, in contrast to classical MHC molecules, monomorphic and, in mammalians, strongly conserved molecule. In humans, it is expressed by most of nucleated cells in which it is kept in the endoplasmic reticulum until binding of an antigen. On the cell surface, there is generally low numbers of MR1, but it can be increased during infection of the cell.^[2]

MR1 binds different classes of ligands.

• The pyrimidine-based molecules with aromatic heterocyclic rings containing nitrogen at positions 1 and 3, such as doxofylline and mercaptopurine.^[1]
• The molecules with a pteridine ring containing a keto group at position 4 and amino group at positions 2, such as 6-formylpterine and acetyl-6-formylpterine.^[1]
• Small aromatic molecules, mostly drugs and drug-like metabolites, such as Aspirin, 3-formyl-salycilic acid and Diclofenac.^[1]

• Microbial antigens, mostly compounds of the riboflavin pathway, such as 7- hydroxy-6-methyl-8-D-ribityllumazine (RL-6-Me-7-OH) and 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU).^[1]
• Drugs, drug metabolites and drug-like molecules, such as mercaptopurine, 5-formyl-salicylic acid and Aspirin.^[1]
• Self-antigens, probably metabolites abnormally synthesized and accumulated in cells during different conditions.^[1]