MAIT cells are an emerging member of the innate-like T cells abundant in human but scarce in mouse. MAIT cells are implicated in many diseases including infectious, allergic, metabolic, and autoimmune disease as well as cancer. Modeling is a prerequisite for understanding the role of MAIT cells in disease, but the paucity of MAIT cells in mice prevents this. Although MR1 knockout mice have been useful, they lack MAIT cells and other MR1-dependent cells, making it difficult to attribute any functional defect solely to MAIT cells. MAIT cell-specific T cell receptor (TCR) transgenic (Tg) mice suffer from the aberrant expression of PLZF, transcription factor essential for MAIT cell development and function.
We herein report other models based on iPSC. One model consists of adoptive transfer of iPSC-derived MAIT cells (reMAIT cells) into naïve C57BL/6. reMAIT cells are activated, and produce a plethora of cytokines and chemokines upon 5-OP-RU or mMR1-tetramer challenge. Adoptive transfer of reMAIT cells into C57BL/6 renders resistance against the inoculated Lewis Lung Carcinoma (LLC).
Another model consists of the mice harboring either the rearranged TRAV1-2-TRAJ33 (referred as Vα19 mice) or TRBV13-3-D-J (referred as Vβ8 mice) in an allele. Both mice harbor abundant MAIT cells across the tissues, and development of iNKT cells and γδ T cells appears not to be perturbed in Vα19 mice. MAIT cells are activated upon cytokines and/or 5-OP-RU challenge, and produce IFN-γ in these mice.
Inoculation of LLC into Vβ8 mice extends the survival relative to C57BL/6, while Vα19 mice do not. However, adoptive transfer of CD8 T cells from C57BL/6 into Vα19 mice recapitulates the tumor resistance. These results indicate that MAIT cells are anti-tumor.
The models open novel horizons for exploring the function of MAIT cells in health and disease and their therapeutic use.