TY - JOUR
T1 - The effect of MR1 ligand glyco-analogues on mucosal-associated invariant T (MAIT) cell activation
AU - Braganza, Chriselle D.
AU - Shibata, Kensuke
AU - Fujiwara, Aisa
AU - Motozono, Chihiro
AU - Sonoda, Koh Hei
AU - Yamasaki, Sho
AU - Stocker, Bridget L.
AU - Timmer, Mattie S.M.
N1 - Funding Information:
B. L. S. would like to thank the Health Research Council of New Zealand for financial support (HRC Hercus Fellowship, 13/049). K. S. (2nd author) would like to thank JSPS for financial support (Grant Number JP 16K08740) and Prof. Yasunobu Yoshikai (Kyushu University, Japan) for providing the opportunity to undertake this work. K. S. (5th author) would like to thank JSPS for financial support (Grant number 26293373). S. Y. would like to thank MEXT (Grant number 26110009) and AMED (Grant number JP17gm0910010 and JP17ak0101070) for financial support. We would like to thank Prof. Olivier Lantz for the provision of 6C2 αβTCR genes. C. D. B. would like to thank Jordan McCone for help with the docking software and Makoto Seiki for technical support.
Publisher Copyright:
© 2019 The Royal Society of Chemistry.
PY - 2019
Y1 - 2019
N2 - Mucosal-associated invariant T (MAIT) cells are a subset of recently identified innate-like T lymphocytes that appear to play an important role in many pathologies ranging from viral and bacterial infection, to autoimmune disorders and cancer. MAIT cells are activated via the presentation of ligands by MR1 on antigen presenting cells to the MAIT T cell receptor (TCR), however few studies have explored the effects of systematic changes to the ligand structure on MR1 binding and MAIT cell activation. Herein, we report on the first study into the effects of changes to the sugar motif in the known MAIT cell agonists 7-hydroxy-6-methyl-8-d-ribityllumazine (RL-6-Me-7-OH) and 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU). Tetramer staining of MAIT cells revealed that the absence of the 2′-hydroxy group on the sugar backbone of lumazines improved MR1-MAIT TCR binding, which could be rationalised using computational docking studies. Although none of the lumazines activated MAIT cells, all 5-OP-RU analogues showed significant MAIT cell activation, with several analogues exhibiting comparable activity to 5-OP-RU. Docking studies with the 5-OP-RU analogues revealed different interactions between the sugar backbone and MR1 and the MAIT TCR compared to those observed for the lumazines and confirmed the importance of the 2′-hydroxy group for ligand binding and activity. Taken together, this information will assist in the development of future potent agonists and antagonists of MAIT cells.
AB - Mucosal-associated invariant T (MAIT) cells are a subset of recently identified innate-like T lymphocytes that appear to play an important role in many pathologies ranging from viral and bacterial infection, to autoimmune disorders and cancer. MAIT cells are activated via the presentation of ligands by MR1 on antigen presenting cells to the MAIT T cell receptor (TCR), however few studies have explored the effects of systematic changes to the ligand structure on MR1 binding and MAIT cell activation. Herein, we report on the first study into the effects of changes to the sugar motif in the known MAIT cell agonists 7-hydroxy-6-methyl-8-d-ribityllumazine (RL-6-Me-7-OH) and 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU). Tetramer staining of MAIT cells revealed that the absence of the 2′-hydroxy group on the sugar backbone of lumazines improved MR1-MAIT TCR binding, which could be rationalised using computational docking studies. Although none of the lumazines activated MAIT cells, all 5-OP-RU analogues showed significant MAIT cell activation, with several analogues exhibiting comparable activity to 5-OP-RU. Docking studies with the 5-OP-RU analogues revealed different interactions between the sugar backbone and MR1 and the MAIT TCR compared to those observed for the lumazines and confirmed the importance of the 2′-hydroxy group for ligand binding and activity. Taken together, this information will assist in the development of future potent agonists and antagonists of MAIT cells.
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U2 - 10.1039/c9ob01436e
DO - 10.1039/c9ob01436e
M3 - Article
C2 - 31497838
AN - SCOPUS:85073482817
SN - 1477-0520
VL - 17
SP - 8992
EP - 9000
JO - Organic and Biomolecular Chemistry
JF - Organic and Biomolecular Chemistry
IS - 40
ER -
