Unstable FoxP3 ⁺ T regulatory cells in NZW mice

Abstract

Regulatory T (Treg) cells that express the transcription factor FoxP3 play a key role in self-tolerance and the control of inflammation. In mice and humans, there is a wide interindividual range in Treg frequency, but little is known about the underlying genetic or epigenetic mechanisms. We explored this issue in inbred strains of mice, with a special focus on the low proportion of Treg cells found in NZW mice. Mixed bone marrow chimera experiments showed this paucity to be intrinsic to NZW Treg cells, a dearth that could be tied to poor stability of the Treg pool and of FoxP3 expression. This instability was not a consequence of differential epigenetic marks, because Treg-specific CpG hypomethylation profiles at the Foxp3 locus were similar in all strains tested. It was also unrelated to the high expression of IFN signature genes in NZW, as shown by intercross to mice with an Ifnar1 knockout. NZW Tregs were less sensitive to limiting doses of trophic cytokines, IL-2 and -33, for population homeostasis and for maintenance of FoxP3 expression. Gene-expression profiles highlighted specific differences in the transcriptome of NZW Tregs compared with those of other strains, but no single defect could obviously account for the instability. Rather, NZW Tregs showed a general up-regulation of transcripts normally repressed in Treg cells, and we speculate that this network-level bias may account for NZW Treg instability.Treg homeostasis | FoxP3 stability | immunoregulation | inbred mice

Plasmacytoid dendritic cells from parent strains of the NZB/W F1 lupus mouse contribute different characteristics to autoimmune propensity

“…It has recently been reported that NZW mice have fewer Foxp3 + CD25 + regulatory T cells (Treg), a finding we confirmed here (Figure a). As we have shown above that NZB mice have increased numbers of pDCs, especially CD8 + pDCs, we investigated whether removal of pDCs in NZB would affect Treg numbers.…”

“…Two recent reports have cogently confirmed the pivotal role of pDCs whereby genetic or pharmacological ablation of pDCs prevents lupus development in murine models . Even though the genes involved in producing the lupus phenotype in NZB/W F1 mice have been known for twenty years, the cellular contributions of the parent strains remain undefined, although various abnormalities have been noted in T and B cells …”

“…Loss of DC led to a loss of Treg, and the DC‐dependent loss in Treg led to a heightened inflammatory response . In the context of autoimmunity of NZB/W mice, NZW mice have been shown to have Treg deficiency . Thus, the marked difference in CD8 + pDCs between NZW and NZB mice prompted us to examine the contribution of pDCs to Treg homeostasis.…”

“…6,7 Even though the genes involved in producing the lupus phenotype in NZB/W F1 mice have been known for twenty years, the cellular contributions of the parent strains remain undefined, although various abnormalities have been noted in T and B cells. [28][29][30][31] The most pronounced difference in the pDCs of NZB is the higher proportion of CD8 + fraction. Although CD8 + pDCs are often described as a subset, 32 questions remain as to the stability of such a subset given that CD8 expression by pDCs is readily induced by activation 33,34 (Supplementary figure 3).…”

BPTF Is Essential for T Cell Homeostasis and Function

“…This can occur in inflammatory environment such as MOG-induced EAE, SLE or diabetes (38–40). Here we found that BPTF is required for the stability of Foxp3 expression.…”