Bcl11b is essential for licensing Th2 differentiation during helminth infection and allergic asthma

Abstract

During helminth infection and allergic asthma, naive CD4+ T-cells differentiate into cytokine-producing Type-2 helper (Th2) cells that resolve the infection or induce asthma-associated pathology. Mechanisms regulating the Th2 differentiation in vivo remain poorly understood. Here we report that mice lacking Bcl11b in mature T-cells have a diminished capacity to mount Th2 responses during helminth infection and allergic asthma, showing reduced Th2 cytokines and Gata3, and elevated Runx3. We provide evidence that Bcl11b is required to maintain chromatin accessibility at Th2-cytokine promoters and locus-control regions, and binds the Il4 HS IV silencer, reducing its accessibility. Bcl11b also binds Gata3-intronic and downstream-noncoding sites, sustaining the Gata3 expression. In addition, Bcl11b binds and deactivates upstream enhancers at Runx3 locus, restricting the Runx3 expression and its availability to act at the Il4 HS IV silencer. Thus, our results establish novel roles for Bcl11b in the regulatory loop that licenses Th2 program in vivo.

Bcl11b prevents fatal autoimmunity by promoting T reg cell program and constraining innate lineages in T reg cells

“…5A), similarly to conventional CD4 + T cells ( 28 ). In line with our previous observations in conventional CD4 + T cells ( 28 ), motif analysis showed that the top 2 motifs were ETS (E26 transformation-specific) and Runx (Runt-related transcription factor) (fig. S4).…”

“…We further performed Bcl11b chromatin immunoprecipitation sequencing (ChIP-seq) analysis on T reg cells to identify genes directly controlled by Bcl11b, which we compared with Bcl11b genomic binding in naïve CD4 + T cells ( 28 ). Given that numerous genes regulated by Bcl11b are also known Foxp3 targets, we also compared the genomic binding by Bcl11b with Foxp3 binding in T reg cells ( 35 ).…”

“…ChIP-seq and ATAC-seq track scale bar normalized to sequences per million reads. ( E ) Venn diagram of Bcl11b ChIP-seq peaks from T reg and naïve CD4 + T cells ( 28 ) at T reg signature genes. ( F ) Peak annotation of differentially accessible ATAC-seq peaks between T reg cells of Bcl11b/T reg KO mosaic and HT mosaic female mice.…”

“…In addition, Bcl11b is required for invariant natural killer T (iNKT) cell development by controlling the glycolipid processing and presentation by double-positive (DP) thymocytes and the functional program of iNKT cells ( 25 , 26 ). Removal of Bcl11b from mature T cells leads to multiple defects including the derepression of the T helper 2 (T H 2) program in T H 17 cells ( 27 ) and failure of T H 2 cells to differentiate during asthma and antihelminth responses ( 28 ). Absence of Bcl11b in innate lymphoid cells type 2 (ILC2) results in loss of their identity and derepression of the ILC3 program ( 29 ).…”

Regulation of Adaptive Immune Cells by Sirtuins

“…Pharmacological SIRT1 inhibition contributed to decreased allergic inflammation in BALB/c mice exposed to ovalbumin via aerosol (40). In addition, mice that exhibit KO of a transcriptional activator essential for Th2 differentiation (B-cell lymphoma/leukemia 11B; Bcl11b) have been found to be protected against EAE (41). Bcl11b is a transcriptional repressor and likely functions by recruiting SIRT1 for histone deacetylase activity (42).…”