Functional analysis of an opioid precursor gene expressed in regulatory T cells

概要

［課程－２］

審査の結果の要旨

氏名リヤン ベンラリビ

A disbalance between stimulatory and inhibitory cues can result in autoimmunity, in
order to add to the bigger picture of the mechanisms controlling the intensity and
dynamics of immune responses, this study addresses the role of an opioid precursor
gene in the course of autoimmune demyelinating inflammation of the central nervous
system. Here, using single-cell RNA sequencing reanalysis and CRISPR–Cas9-based
cell-specific in vivo genetic perturbations in mice, we identified a novel signal molecule
expressed in regulatory T cells that limits the suppression of chronic immune
responses. We found that total genetic inactivation of proenkephalin (Penk) resulted in
an amelioration of experimental autoimmune encephalomyelitis (EAE) symptoms
during the chronic phase. We identified regulatory T cells (Tregs) as the main immune
cell expressing Penk in homeostasis and in the course of EAE. We found that the
specific deletion of Penk in Tregs recapitulated EAE amelioration seen in Penk total
KO mice with the same amplitude, indicating that loss of Penk function in Tregs is
responsible for the amelioration of chronic autoimmunity. Thus, our findings suggest a
novel negative feedback loop in Tregs to counterbalance the suppression of immune
responses. The findings in this study are thought to open new avenues for the
treatment of autoimmune diseases.
よって本論文は博士（ 医学 ）の学位請求論文として合格と認められる。