Abstract
The transcriptional regulator Rbpj is involved in T-helper (TH) subset polarization, but its function in Treg cells remains unclear. Here we show that Treg-specific Rbpj deletion leads to splenomegaly and lymphadenopathy despite increased numbers of Treg cells with a polyclonal TCR repertoire. A specific defect of Rbpj-deficient Treg cells in controlling TH2 polarization and B cell responses is observed, leading to the spontaneous formation of germinal centers and a TH2-associated immunoglobulin class switch. The observed phenotype is environment-dependent and can be induced by infection with parasitic nematodes. Rbpj-deficient Treg cells adopt open chromatin landscapes and gene expression profiles reminiscent of tissue-derived TH2-polarized Treg cells, with a prevailing signature of the transcription factor Gata-3. Taken together, our study suggests that Treg cells require Rbpj to specifically restrain TH2 responses, including their own excessive TH2-like differentiation potential.
Highlights
The transcriptional regulator Rbpj is involved in T-helper (TH) subset polarization, but its function in Treg cells remains unclear
We closely monitored our mice for 20 weeks, and about 40% of mice spontaneously developed splenomegaly and lymphadenopathy within this time interval, while about 60% of animals remained healthy (Fig. 1a, b)
Lymph nodes and spleen from Δ/Δ animals harbored about 10–20 times more Treg cells than their WT counterparts (Fig. 1c, right panel)
Summary
The transcriptional regulator Rbpj is involved in T-helper (TH) subset polarization, but its function in Treg cells remains unclear. A specific defect of Rbpj-deficient Treg cells in controlling TH2 polarization and B cell responses is observed, leading to the spontaneous formation of germinal centers and a TH2-associated immunoglobulin class switch. Rbpj-deficient Treg cells adopt open chromatin landscapes and gene expression profiles reminiscent of tissue-derived TH2-polarized Treg cells, with a prevailing signature of the transcription factor Gata-3. In contrast to this, forced expression of the NICD in Treg cells rendered them incapable of suppressing T effector cells and caused autoimmunity[20] This indicates that, based on the cellular context, Rbpj and Notch have a different impact on cellular responses. Loss of Rbpj renders Treg cells more sensitive to TH2-inducing conditions and fosters the extensive generation of Gata-3-positive tissue-type Treg cells
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