Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4+ T cell identity and function.
Jayati BasuBernardo Sgarbi ReisSuraj PeriJikun ZhaXiang HuaLu GeKyle FerchenEmmanuelle NicolasPhilip CzyzewiczKathy Q CaiYinfei TanJuan I Fuxman BassAlbertha J M WalhoutH Leighton GrimesSergei I GrivennikovDaniel MucidaDietmar J KappesPublished in: Nature immunology (2021)
The transcription factor ThPOK (encoded by the Zbtb7b gene) controls homeostasis and differentiation of mature helper T cells, while opposing their differentiation to CD4+ intraepithelial lymphocytes (IELs) in the intestinal mucosa. Thus CD4 IEL differentiation requires ThPOK transcriptional repression via reactivation of the ThPOK transcriptional silencer element (SilThPOK). In the present study, we describe a new autoregulatory loop whereby ThPOK binds to the SilThPOK to maintain its own long-term expression in CD4 T cells. Disruption of this loop in vivo prevents persistent ThPOK expression, leads to genome-wide changes in chromatin accessibility and derepresses the colonic regulatory T (Treg) cell gene expression signature. This promotes selective differentiation of naive CD4 T cells into GITRloPD-1loCD25lo (Triplelo) Treg cells and conversion to CD4+ IELs in the gut, thereby providing dominant protection from colitis. Hence, the ThPOK autoregulatory loop represents a key mechanism to physiologically control ThPOK expression and T cell differentiation in the gut, with potential therapeutic relevance.
Keyphrases
- transcription factor
- gene expression
- genome wide
- poor prognosis
- dna methylation
- genome wide identification
- dna binding
- induced apoptosis
- nk cells
- binding protein
- regulatory t cells
- high grade
- stem cells
- immune response
- hiv infected
- cell proliferation
- long non coding rna
- mesenchymal stem cells
- heat shock
- endoplasmic reticulum stress
- genome wide analysis