Restricting the development of autoimmune disease by skewing the pathogenic th17 cells to protective tregs

Abstract

During multiple sclerosis, MOG35-55 reactive pathogenic Th17 cells destroy the myelin sheath surrounding nerve fibers. There is no vaccine or durable cure for the disease. Rapamycin has the remarkable ability to differentiate stimulated naïve T cells into regulatory T cells (Tregs). In this study, we exploited on rapamycin's unique property to transform MOG35-55 reactive pathogenic Th17 cells into MOG35-55 specific protective Tregs. We demonstrated that mice, which were vaccinated with a combination of MOG35-55 and rapamycin, displayed no symptoms of experimental autoimmune encephalomyelitis (EAE) upon re-exposure to a morbific dose of MOG35-55. Notably, there was a significant increase in the population of MOG35-55-specific memory Tregs that primarily expressed immunosuppressive phenotype (CD39hi, CD73hi, PD1hi, Tim3hi, and IL-10hi). This was accompanied by a substantial decline in the population of Th17 cells. Additionally, a substantial increase in the pool of myeloid derived suppressor cells (MDSC) with the suppressive phenotype (TGF-βhi, IL-10hi, CD103hi, LFA-1lo, and FasLhi) was observed. The underlying mechanism of this phenomenon was deciphered to be through autophagy; as evidenced by the modulation of autophagy markers mTORlo, FIP200hi, Atg13hi, ULK1hi, beclinhi, and LC3hi in both Tregs and MDSC. This study introduces a novel stratagem to revert pathogenic MOG35-55 reactive Th17 cells towards protective MOG35-55 specific Tregs through rapamycin. In the future, this study has the potential to open new avenues for developing a vaccine to protect and cure multiple sclerosis.