Flash Talk & Poster CD1-MR1 2024

The regulation of human MAIT cell cytolytic protein expression and cytotoxicity by various cytokines (#235) (#72)

Yiting Xue 1 2 , Zhenyu Liu 2 3 , Fei Han 1 2 , Amanda Ho 1 2 , Dan He 1 2 , Huizhong Xu 1 2 , Edwin Leeansyah 1 2
  1. Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen 518055, China
  2. Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
  3. School of Medicine, Tsinghua University, Beijing 100084, China

Mucosa-associated invariant T (MAIT) cells are innate-like T cells known for their rapid and potent antimicrobial activity. Upon recognizing bacteria-derived riboflavin metabolites presented by MHC class Ib protein (MR1), MAIT cells rapidly respond by secreting pro-inflammatory cytokines and cytolytic proteins. The antimicrobial activity of MAIT cells is partly dependent on the activity of the cytolytic proteins Perforin (Prf), Granzyme B (GrzB), and Granulysin (Gnly). Various cytokines regulate MAIT cell activation during bacterial infection. Given that the levels of cytolytic proteins secreted by MAIT cells correlate with MAIT cell antimicrobial activity, here we investigated the effect of various cytokines on the regulation of these cytolytic proteins in MAIT cells.

Here, we investigated the effect on cytolytic protein regulation by IL-1β, IL-2, IL-7, IL-12, IL-15, IL-18, and IL-23. Considering the potential synergistic effects performed by these cytokines, we further extended our findings by using distinct combinations of these cytokines for MAIT cell stimulation, including IL-12+IL-18, IL-1β+IL-23, IL-2+IL-7, and IL-2+IL-7+IL-15. In the presence of MR1 ligands, these cytokine treatments induced substantial proliferation of MAIT cells, while upregulated Prf, GrzB, and Gnly expression by MAIT cells at different rates and magnitudes. We further demonstrated that various cytokine stimuli resulted in different levels of MAIT cells-mediated cytotoxicity, with IL-15 having the strongest effect on MAIT cells killing of target cells pulsed with MR1 ligands. The administration of multiple cytokines diminished the TCR-dependency in MAIT cell-mediated cytotoxicity compared to MAIT cells treated with individual cytokines.

These results indicate that there are temporal and differential effects by various cytokines on MAIT cell expression of cytolytic protein expression and MAIT cell-mediated antimicrobial activity. Going forward, further optimization of MAIT cell cytolytic and antimicrobial responses is necessary, that will be important for the future development of a safe and effective MAIT cells-based antimicrobial therapy.