Abstract
Mutations disrupting regulatory T (Treg) cell function can cause IPEX and IPEX-related disorders, but whether established disease can be reversed by correcting these mutations is unclear. Treg-specific deletion of the chromatin remodeling factor Brg1 impairs Treg cell activation and causes fatal autoimmunity in mice. Here, we show with a reversible knockout model that re-expression of Brg1, in conjunction with the severe endogenous proinflammatory environment, can convert defective Treg cells into powerful, super-activated Treg cells (SuperTreg cells) that can resolve advanced autoimmunity, with Brg1 re-expression in a minor fraction of Treg cells sufficient for the resolution in some cases. SuperTreg cells have enhanced trafficking and regulatory capabilities, but become deactivated as the inflammation subsides, thus avoiding excessive immune suppression. We propose a simple, robust yet safe gene-editing-based therapy for IPEX and IPEX-related disorders that exploits the defective Treg cells and the inflammatory environment pre-existing in the patients.
Highlights
Mutations disrupting regulatory T (Treg) cell function can cause IPEX and IPEX-related disorders, but whether established disease can be reversed by correcting these mutations is unclear
This cassette was inserted into intron #9 (Fig. 1b), capturing the upstream exon #8 (E8) to produce a fusion protein between the N-terminal 531 aa of BRG1 protein and the neomycin phosphotransferase, the former moiety being inactive, and the latter serving as the selection marker for successfully targeted embryonic stem (ES) cells
In Brg1F/ΔR mice that expressed Cre in Treg cells and FlpoER, Brg[1] expression is constitutively eliminated in Treg cells but reinstated upon tamoxifen (TAM) administration, the latter event reported by elimination of GFP fluorescence (Fig. 1a, middle and bottom)
Summary
Mutations disrupting regulatory T (Treg) cell function can cause IPEX and IPEX-related disorders, but whether established disease can be reversed by correcting these mutations is unclear. Even if all the defective Treg cells in the body could be fully resurrected, it is unclear whether this would be sufficient to resolve the severe ongoing inflammation and rescue the patients, given that the inflammation may have become overwhelming and/or tissue damages irreversible by the time of clinical diagnosis and mutation correction. We have established a reversible Brg[1] KO model, and found that restoring Brg[1] expression in the mice can produce therapeutic effects, with Brg[1] reexpression in only minor fractions (as low as 8%) of Treg cells sufficient for rescuing the mice with slightly less severe phenotypes, suggesting a simple, robust, and safe approach for treating IPEX and IPEX-like diseases
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