The transcription factor TCF-1 initiates the differentiation of TFH cells during acute viral infection

Abstract

Induction of the transcriptional repressor Bcl-6 in CD4(+) T cells is critical for the differentiation of follicular helper T cells (T(FH) cells), which are essential for B cell-mediated immunity. In contrast, the transcription factor Blimp1 (encoded by Prdm1) inhibits T(FH) differentiation by antagonizing Bcl-6. Here we found that the transcription factor TCF-1 was essential for both the initiation of T(FH) differentiation and the effector function of differentiated T(FH) cells during acute viral infection. Mechanistically, TCF-1 bound directly to the Bcl6 promoter and Prdm1 5' regulatory regions, which promoted Bcl-6 expression but repressed Blimp1 expression. TCF-1-null T(FH) cells upregulated genes associated with non-T(FH) cell lineages. Thus, TCF-1 functions as an important hub upstream of the Bcl-6-Blimp1 axis to initiate and secure the differentiation of T(FH) cells during acute viral infection.

Mst1 positively regulates B-cell receptor signaling via CD19 transcriptional levels

“…Chromatin fragments were prepared as described, 25 followed by immunoprecipitation with TEAD2 Antibody (H-50): sc-67115 or rabbit immunoglobulin G (IgG; A7016; Beyotime) coupled to Dynabeads Protein G (10004D; Life Technologies) with previous protocol. 26 …”

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.…”

Integrated STAT3 and Ikaros Zinc Finger Transcription Factor Activities Regulate Bcl-6 Expression in CD4+ Th Cells

“…Specifically, STAT1, STAT3, and STAT4 have been shown to positively regulate Bcl-6 expression, while STAT5 is a demonstrated repressor of Bcl-6(21, 31). Beyond STAT factors, additional transcriptional regulators including Batf and Tcf-1 have been shown to induce Bcl-6 expression (32-35). Despite these important insights, many questions remain regarding the identity of the transcriptional network that regulates Bcl-6 expression in CD4 + T cell populations.…”