Deciphering the newly discovered immunoregulatory mechanisms of human MAIT cells for adoptive immunotherapy in allogeneic settings – MAITREG

Adoptive cellular immunotherapy has emerged as a fascinating approach to prevent and/or limit graft-versus-host disease (GVHD), a major source of morbidity and mortality following allogeneic transplantation. To date however, the most appropriate regulatory population to use remains elusive. Human mucosal associated invariant T cells (MAITs) are unconventional T cells very abundant in barrier tissues and blood, which express a semi-invariant TCR recognizing microbial-derived riboflavin derivatives presented by the highly conserved MR1 molecule. MAITs exhibit potent TCR-dependent and -independent effector functions in response to homeostatic perturbations. Recent studies have also revealed the tissue repair and regulatory capacities of MAITs, but the mechanisms involved in these new functions are hardly explored. We recently demonstrated that MAITs lack alloreactive potential and do not contribute to GVHD tissue lesions, prompting us to exploit their regulatory potential for adoptive cell therapy in allogeneic settings. Our program has three specific objectives: 1/ to characterize the MAIT regulatory mechanisms in vitro in a mixed lymphocyte reaction (MLR) model using transcriptomic, deep phenotyping and live microscopy, 2/ to confirm the mechanisms sustaining the protective role of human MAITs in vivo in a xenogenic GVHD model, and 3/ to validate the identified molecule(s) using gene-edited MAITs or specific antagonists. A main challenge of our project will be to determine if MAITs perform dual effector and regulatory functions depending on the inflammatory context. Our results should allow considering human MAITs as universal, off-the-shelf therapeutic tools to control GVHD or other inflammatory mucosal diseases.