MAIT cells activate dendritic cells to promote TFH cell differentiation and induce humoral immunity

Targeting MAIT cells as a cellular adjuvant for humoral immunity: a new player in a very old game

“…A recent paper by Pankhurst et al, led by the laboratory of Dr Lisa Connor at the Victoria University of Wellington, demonstrates that experimental delivery of a strong MR1 ligand can serve as an adjuvant to induce antibody responses against a codelivered protein antigen. 2 These data provide proof-of-concept that MAIT cells can be specifically targeted for vaccine purposes and adds yet another aspect to the growing list of MAIT cell functions.…”

Establishment of an MR1 Presentation Reporter Screening System and Identification of Phenylpropanoid Derivatives as MR1 Ligands

“…Then, using a procedure similar to that described for synthesis of 10 from S2, the crude acetal S4 (46.8 mg) was converted into the aldehyde 11 (16.1 mg, 27% yield, 2 steps). Column chromatography: silica gel (gradient 6−30% EtOAc in n-hexane): pale yellow solid; mp 131−133 °C; IR (neat cm −1 ): 3212 (OH), 1658 (C�O); 1 H NMR (500 MHz, CDCl 3 ): δ 5.74 (s, 1H), 6.84−6.86 (m, 1H), 6.92 (dd, J = 16.0, 8.0 Hz, 1H), 6.98−7.01 (m, 1H), 7.30−7.33 (m, 1H), 7.53 (dd, J = 7.7, 1.4 Hz, 1H), 7.80 (d, J = 16.0 Hz, 1H), 9.70 (d, J = 8.0 Hz, 1H); 13 (E)-3-(4-Methoxyphenyl)acrylaldehyde (12). Using a procedure identical with that described for synthesis of S2 from S1, the benzaldehyde S5 (136 mg, 1.00 mmol) was converted into a crude S6 (89.2 mg), which was used without further purification.…”

“…In contrast, 6-FP, a vitamin B9 metabolite, is an MR1 binder and competes with MAIT cell activators, leading to inhibition of the MR1−MAIT cell axis. 12 Additionally, several synthetic 6-FP derivatives were reported, such as acetyl 6-formylpterin (Ac-6-FP) and i6-FP (Figure S1). 13 Regarding drugs and drug-like molecules, Keller et al identified diclofenac and 5-formylsalicylic acid (5-F-SA) as an activator and an inhibitor, respectively, suggesting that the side effects and hypersensitivity caused by these drugs may be associated with the regulation of MAIT cell functions.…”

“…In chronic pathological situations, including autoimmune or inflammatory diseases, MAIT cells can play a pathogenic role by sustaining inflammation and cytotoxicity. − Therefore, MR1 ligands (antigens binding to MR1) that exhibit agonistic or antagonistic activities toward MAIT cell functions could serve as potential drug candidates for infectious diseases, and various disorders such as colorectal cancer, lupus, or multiple sclerosis. Indeed, Pankhurst et al reported that 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU, a MAIT cell activator, vide infra ) was effective as a vaccine adjuvant via the activation of dendritic cells to promote T follicular helper cell differentiation and humoral immunity . In contrast, Murayama et al demonstrated that the inhibition of MAIT cell activation by treatment with isobutyryl 6-formylpterin (i6-FP, vide infra ) had beneficial effects on the disease course of lupus …”

“…Although 5-OP-RU is a short-lived compound, the X-ray crystal structure of the MR1/5-OP-RU/TCR ternary complex was reported, providing information about the molecular recognition mechanism. In contrast, 6-FP, a vitamin B9 metabolite, is an MR1 binder and competes with MAIT cell activators, leading to inhibition of the MR1–MAIT cell axis . Additionally, several synthetic 6-FP derivatives were reported, such as acetyl 6-formylpterin (Ac-6-FP) and i6-FP (Figure S1).…”