Flash Talk & Poster CD1-MR1 2024

Novel MAIT cell-intestinal organoid coculture system to explore the mechanisms of circulating MAIT cell migration into gastrointestinal tissues during acute inflammation (#248) (#41)

Zhengyu Wu 1 , Yichao Zheng 1 2 , Fei Han 1 , Xingchi Chen 1 , Dan He 1 2 , Yiting Xue 1 2 , Caroline Boulouis 3 , Bingjie Wang 4 , Johan Sandberg 3 , Shaohua Ma 1 , Edwin Leeansyah 1
  1. Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
  2. Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen 518055, China
  3. Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, 14152 Stockholm, Sweden
  4. Department of Pediatric Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou 363000, China

Mucosa-associated invariant T (MAIT) cells are the largest population of antimicrobial T cells in humans. MAIT cells are widely distributed along the human gastrointestinal tract (GIT) and play fundamental roles in GIT mucosal immunity. Circulating MAIT cells can migrate into the gut tissues during various GIT infections and inflammation. However, there is a lack of knowledge on the mechanisms underlying MAIT cell migration to gut mucosal tissues in these pathological conditions.

 

Here, we developed a three-dimensional (3D)-intestinal organoid model to test the migratory potential of human MAIT cells and other lymphocyte populations from the peripheral blood. The results indicated that innate-like lymphocytes were particularly enriched within the intestinal organoids, including MAIT, NK, and γδT cells. Time-lapse confocal live imaging and microscopy revealed the rapid migration and infiltration of MAIT cells into the 3D intestinal organoids.

 

Next, we established patient-derived 3D-appendix organoid (PDO) cultures from appendicitis patients to examine the mechanism of circulating MAIT cell migration during acute inflammation. Secretomes from the 3D-appendix PDO cultures contained high levels of inflammatory and gut tissue-associated cytokines and chemokines. Interestingly, treatment of MAIT cells with such cytokines led to the upregulation of multiple inflammatory chemokine receptors, including CCR1, CCR3, and CCR4, and led to markedly enhanced migration toward the intestinal organoids. Finally, using various chemokine receptor pharmacological inhibitors, we found that circulating MAIT cells primed with these inflammatory cytokines rapidly migrated in response to stimulation using original PDO supernatants through CCR1-, CCR2-, and CCR4-mediated pathways.

 

In summary, using the 3D intestinal organoid models, we discovered novel mechanisms underlying MAIT cell migration into the gut tissues during acute infection and inflammation. Going forward, such models may be a suitable tool to evaluate the mechanisms of MAIT cell tissue-homing and understand their potential roles in GI tissue homeostasis, infection, and inflammation.