Abstract
AbstractRegulatory T cells (Tregs) are an immunosuppressive population that are identified based on the stable expression of the fate-determining transcription factor forkhead box P3 (Foxp3). Tregs can be divided into distinct subsets based on whether they developed in the thymus (tTregs) or in the periphery (pTregs). Whether there are unique functional roles that distinguish pTregs and tTregs remains largely unclear. To elucidate these functions, efforts have been made to specifically identify and modify individual Treg subsets. Deletion of the conserved non-coding sequence (CNS)1 in the Foxp3 locus leads to selective impairment of pTreg generation without disrupting tTreg generation in the C57BL/6J background. Using CRISPR-Cas9 genome editing technology, we removed the Foxp3 CNS1 region in the non-obese diabetic (NOD) mouse model of spontaneous type 1 diabetes mellitus (T1D) to determine if pTregs contribute to autoimmune regulation. Deletion of CNS1 impaired in vitro induction of Foxp3 in naïve NOD CD4+ T cells, but it did not alter Tregs in most lymphoid and non-lymphoid tissues analyzed except for the large intestine lamina propria, where a small but significant decrease in RORγt+ Tregs and corresponding increase in Helios+ Tregs was observed in NOD CNS1−/− mice. CNS1 deletion also did not alter the development of T1D or glucose tolerance despite increased pancreatic insulitis in pre-diabetic female NOD CNS1−/− mice. CNS1 Furthermore, the proportions of autoreactive Tregs and conventional T cells (Tconvs) within pancreatic islets were unchanged. These results suggest that pTregs dependent on the Foxp3 CNS1 region are not the dominant regulatory population controlling T1D in the NOD mouse model.
Publisher
Cold Spring Harbor Laboratory
Reference63 articles.
1. Sakaguchi, Shimon ; Sakaguchi, Noriko ; Asano Masanao ; Itoh, Misako ; Toda M . Immunologic Self-Tolerance Maintained by activated T cells expressing IL-2 Receptor a-chains (CD25). J Immunol. 1995;
2. Takahashi T , Tagami T , Yamazaki S , Uede T , Shimizu J , Sakaguchi N , et al. Immunologic Self-Tolerance Maintained by Cd25 + Cd4 + Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte–Associated Antigen 4. J Exp Med. 2000;
3. Control of Regulatory T Cell Development by the Transcription Factor
Foxp3
4. Fontenot JD , Gavin MA , Rudensky AY . Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat Immunol. 2003;
5. Regulatory T Cell Lineage Specification by the Forkhead Transcription Factor Foxp3
Cited by
3 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献