Highlights d Two precursor stages of ST2 + nonlymphoid-tissue Tregs are evident in the spleen and LNs d Precursor stages are defined by differential expression of Nfil3, PD1, and Klrg1 d Chromatin accessibility and scRNA-seq suggests a stepwise precursor reprogramming d Batf drives the molecular tissue program in the precursors Authors
Highlights d Comparison of chromatin accessibility between murine und human tissue Treg cells d TCR tracking revealed clonal relationship between tissue and blood BATF + CCR8 + Tregs d Treg cells from healthy tissues were similar to CCR8 + Treg cells from tumors d Tfh-like differentiation program induces tissue Treg cell repair characteristics
The transcriptional regulator Rbpj is involved in T-helper (T
H
) subset polarization, but its function in T
reg
cells remains unclear. Here we show that T
reg
-specific Rbpj deletion leads to splenomegaly and lymphadenopathy despite increased numbers of T
reg
cells with a polyclonal TCR repertoire. A specific defect of Rbpj-deficient T
reg
cells in controlling T
H
2 polarization and B cell responses is observed, leading to the spontaneous formation of germinal centers and a T
H
2-associated immunoglobulin class switch. The observed phenotype is environment-dependent and can be induced by infection with parasitic nematodes. Rbpj-deficient T
reg
cells adopt open chromatin landscapes and gene expression profiles reminiscent of tissue-derived T
H
2-polarized T
reg
cells, with a prevailing signature of the transcription factor Gata-3. Taken together, our study suggests that T
reg
cells require Rbpj to specifically restrain T
H
2 responses, including their own excessive T
H
2-like differentiation potential.
Death Receptor 3 (DR3) and its cognate ligand TL1A belong to the tumor necrosis factor superfamily (TNFSF). This sophisticated network of receptor-ligand systems controls innumerable biological processes. For many (if not all) TNFSF ligands and receptors, a role in conditions such as inflammation, tissue development, proliferation, and cell death has been firmly established. However, relatively little is known about DR3 and TL1A. Here, we review novel aspects of DR3 signaling and DR3-associated signaling pathways before summarizing the function of DR3 in the immune system. The emerging role of DR3 in disease will be addressed before we finally critically discuss the potential therapeutic exploitation of this receptor-ligand pair.
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