LEF-1 and TCF-1 orchestrate TFH differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6

Abstract

T follicular helper (TFH) cells are specialized effector CD4+ T cells that help B cells develop germinal centers and memory. However, the transcription factors that regulate TFH differentiation remain incompletely understood. Here we report that selective loss of either Lef1 (LEF-1) or Tcf7 (TCF-1) resulted in TFH defects, while deletion of Lef1 and Tcf7 severely impaired TFH differentiation and germinal centers. Forced expression of LEF-1 enhanced TFH differentiation. LEF-1 and TCF-1 coordinated TFH differentiation by two general mechanisms. First, they established the responsiveness of naïve CD4+ T cells to TFH signals. Second, they promoted early TFH differentiation via the multipronged approach of sustaining expression of IL-6Rα and gp130, enhancing ICOS expression, and promoting expression of Bcl6.

Bcl6 middle domain repressor function is required for T follicular helper cell differentiation and utilizes the corepressor MTA3

“…Interestingly, the absence of Srg3 led to a small (twofold) increase in Blimp1 expression, resulting in a larger defect (three-to fourfold reduction) in Tfh cell differentiation. We have observed a similarly moderate dysregulation of Blimp1 expression linked with a substantially larger impairment in Tfh cell differentiation here and in a study of Lef1 and Tcf7 (36). These data suggest that small alterations in Prdm1 expression can substantially affect Tfh cell differentiation.…”

“…Primers are listed in Table S3. MTA3 gene expression in Table S1 are from GSE67336 (36). For ChIP, MCC T cells or primary GC Tfh cells were harvested and then cross-linked with 1% formaldehyde.…”

The Costimulatory Molecule ICOS Regulates Host Th1 and Follicular Th Cell Differentiation in Response to Plasmodium chabaudi chabaudi AS Infection

“…Additionally, the literature suggests the involvement of other proteins, such as LEF-1 and TCF-1, in priming Bcl6 induction and T FH cell commitment prior to ICOS signaling (66). Furthermore, the achaete-scute homologue 2 (Ascl2) protein has recently been implicated in promoting early T FH cell localization by enhancing CXCR5 and downregulating CCR7 expression independently of ICOS and Bcl6 (67).…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…Bcl6 plays a central role in Tfh cell differentiation,115, 137, 138 but other transcription factors that act upstream and downstream of Bcl6 are also required (reviewed in 139). These include lymphoid enhancer‐binding factor 1 (LEF‐1) and T‐cell‐specific transcription factor 1 (TCF‐1), which act upstream of Bcl6 to promote Tfh cell differentiation140, 141, 142; basic leucine zipper transcription factor ATF‐like (Batf), which positively regulates Bcl6 and is important for IL‐4 expression143; interferon regulatory factor 4 (IRF4), which drives differentiation of IL‐12‐stimulated CD4 T cells to Tfh rather than Th1 cells144; achaete‐scute homolog 2 (Ascl2), which induces CXCR5 expression145; c‐Maf, which enhances expression of CXCR5, IL‐21, and IL‐4146; signal transducer and activator of transcription (STAT)s, STAT3 and 4 being particularly important for human Tfh cell differentiation and regulation of IL‐21 expression by human CD4 + T cells121, 147; and forkhead box protein O1 (FOXO1), which can both promote and inhibit Tfh cell differentiation 148. In addition, Tfh cell differentiation is regulated by microRNAs including members of the miRNA‐17‐92 family 149, 150.…”