Poster Presentation CD1-MR1 2024

MAIT cell specialization across paired human tissues (#102)

Tobias Kammann 1 , Curtis Cai 1 , Takuya Sekine 1 , Elli Mouchtaridi 1 , Caroline Boulouis 1 , Vera Nilsén 1 , Olga R Ballesteros 1 , Thomas R Müller 1 , Yu Gao 1 , Elisa Raineri 1 , Mily Akhirunnesa 1 , Oriana Ribeiro 1 , Julia Niessl 1 , Whitney Weigel 1 , Anne Marchalot 1 , Christopher Stamper 1 , Efthymia Kokkinou 1 , John Bassett 1 , Inga Rødahl 1 , Nicole Wild 1 , Demi Brownlie 1 , Chris Tibbitt 1 , Jeffrey Y Mak 2 3 , David P Fairlie 2 3 , Edwin Leeansyah 4 5 , Nicole Marquardt 1 , Jakob Michaelsson 1 , Jenny Mjösberg 1 , Carl Jorns 6 7 , Marcus Buggert 1 , Johan K Sandberg 1
  1. Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
  2. Division of Chemistry and Structural Biology, Institute for Molecular BioScience, The University of Queensland, Brisbane, Australia
  3. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Australia
  4. Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, China
  5. Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore
  6. PO Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden
  7. Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden

Mucosa-associated invariant T (MAIT) cells are  unconventional T cells recognizing microbial vitamin B2 metabolites presented by the evolutionarily conserved MR1 molecules to mediate innate-like immune protection of human tissues. Here, we analyzed MAIT cells in human organ donor-matched blood, mucosal barrier- and lymphoid tissues and observed a donor-dependent MAIT cell compartment size across tissues with distinct compartmentalization patterns across body sites. Further, paired data revealed tissue-dependent MAIT cell heterogeneity: Intestinal intra-epithelial MAIT cells presented an immunoregulatory CD39high CD27low phenotype. In contrast, a MAIT cell phenotype expressing the adhesion receptor NCAM1 (CD56) was dominant in the liver and indicative of trained effector capacity. CD56+ MAIT cells demonstrated an increased response magnitude and polyfunctionality following multimodal activation. Immuno-secretome analysis highlighted a CD56+ effector signature supporting tissue homeostasis, immune cell recruitment, and inflammation. CD56+ MAIT cells showed a transcriptional profile skewed towards regulation through innate-like pathways or degranulation and exhibited a reduced TCR repertoire diversity. Importantly, CD56 was dynamically upregulated by MAIT cells to a persistent steady state equilibrium following exposure to antigen or homeostatic IL-7 without the need of proliferation. In summary, we demonstrate MAIT cell heterogeneity across human barrier tissue sites and provide evidence for the emergence of a specialized CD56-associated MAIT cell enhanced effector signature.