Mechanism of Follicular Helper T Cell Differentiation Regulated by Transcription Factors

Table 1

Transcription factors in the differentiation of Tfh cells.

Transcription factors	Abbreviation of transcription factors	Function in Tfh cell differentiation	Signaling pathways	Related diseases
B-cell lymphoma 6 protein	Bcl6	Initiates the differentiation of Tfh cells at the early stage of Tfh cell generation	Be induced by IL-6-STAT1/STAT3 signaling, inhibits the IL-7R/STAT5 axis, suppresses microRNAs (miR-17-92 and miR-31), a direct target of ATF-3	Acute lymphocytic choriomeningitis virus (LCMV) infection [11]
				Chronic immune thrombocytopenia (cITP) [12]
				Systemic lupus erythematosus (SLE) [13]
				IgG4-related disease (IgG4-RD) [14]
				Rheumatoid arthritis (RA) [15]
B lymphocyte maturation protein 1	Blimp-1	Inhibits the differentiation of Tfh cells	Inhibits the expression of Bcl6	IgG4-RD [14]
Activating transcription factor 3	ATF-3	Initiates the differentiation of Tfh cells	Targets Bcl6 in CD4^+T cells	Colitis [16]
c-Musculoaponeurotic-fibrosarcoma	c-Maf	Promotes the differentiation of Tfh cells	c-Maf and Bcl6 synergistically orchestrate genes that define core characteristics of Tfh cell biology	cITP [12]
Basic leucine zipper transcription factor	Batf	Promotes the differentiation of Tfh cells	Regulates the expression of Bcl6 and c-Maf, cooperates with IRF4 during the development of Tfh cells, be regulated by IL-4-STAT6 and IL-6-STAT3 signaling	IgG4-RD [17]
Interferon regulatory factor 4	IRF4	Promotes the differentiation of Tfh cells	Regulates the generation of Tfh cells in a Bcl6-dependent manner, regulates the production of IL-21 and controls most IL-21-regulated genes by IL-21-STAT3 axis	LCMV infection [18]
Interferon regulatory factor 8	IRF8	Inhibits the differentiation of Tfh cells	Binds to the promoter region of IRF4 gene and inhibits transcription and transactivation of IRF4	Inflammatory bowel disease (IBD) [19]
Signal transducers and activators of transcription 1	STAT1	Promotes the differentiation of Tfh cells at the early stage of Tfh cell generation	Regulates the differentiation of Tfh cells by IL-6-STAT1-Bcl6 signaling	Viral infection [20]
				SLE [21, 22]
Signal transducers and activators of transcription 3	STAT3	Promotes the differentiation of Tfh cells	Regulates the expression of Bcl6	RA [23]
Signal transducers and activators of transcription 4	STAT4	Promotes the differentiation of Tfh cells	STAT4 and T-bet are coexpressed with Bcl6 to coordinate the production of IL-21 and IFN-γ by Tfh cells	Acute LCMV infection [24]
				SLE [22]
Signal transducers and activators of transcription 5	STAT5	Inhibits the differentiation of Tfh cells	Downregulates Bcl6 expression and upregulates Blimp-1 expression through IL-2/IL-7/IL-10-STAT5 signaling	LCMV infection [25, 26]
T-box expressed in T cells	T-bet	Mildly inhibits the early differentiation of Tfh cells, but promotes Tfh cell proliferation and apoptotic intervention at the late effector phase	T-bet and STAT4 are coexpressed with Bcl6 to coordinate the production of IL-21 and IFN-γ by Tfh cells	LCMV infection [2, 24, 27]
				SLE [22]
T cell-specific transcription factor 1	TCF-1	Promotes the differentiation of Tfh cells at the early stage of Tfh cell generation	Promotes the expression of Bcl6, but represses the expression of Blimp-1	LCMV infection [7, 28–30]
Lymphoid enhancer binding factor 1	LEF-1	Promotes the differentiation of Tfh cells at the early stage of Tfh cell generation	Works synergistically with TCF-1 to enhance the expression of ICOS and Bcl6	LCMV infection [30]
The high-mobility group- (HMG-) box 2	TOX2	Initiates the differentiation of Tfh cells	Be regulated by Bcl6 and STAT3 in the initial stage of Tfh cell generation, inhibits IL-2 and/or enhances IL-6 signaling to promote Bcl6 expression	Viral infection [31]
Achaete-scute homolog 2	Ascl2	Promotes the differentiation of Tfh cells	Upregulates CXCR5 but not Bcl6 and downregulates CCR7 expression as well as IL-2 signaling	Sjögren syndrome (SS) [32]
BTB and CNC homolog 2	Bach2	Inhibits the differentiation of Tfh cells	Suppresses the expression of Bcl6 by directly binding to the promoter, negatively regulates CXCR5 expression	Viral infection [33, 34]
Forkhead-box protein O1	FOXO1	Inhibits the differentiation of Tfh cells	Negatively regulates the differentiation of Tfh cells through an ICOS-mTORC2-FOXO1 signaling axis in the early stages of differentiation, negatively regulates the expression of Bcl6	Angioimmunoblastic T cell lymphoma induced [35]
Forkhead-box protein P1	FOXP1	Inhibits the differentiation of Tfh cells	Negatively regulates the expression of CTLA-4 and IL-21 in activated CD4^+T cells	LCMV infection [36]
Krüppel-like factor 2	KLF2	Inhibits the differentiation of Tfh cells	Downregulates S1PR1, induces the expression of Blimp-1, miRNA92a-mediated Tfh precursor induction is regulated by PTEN-PI3K-KLF2 signaling	Type 1 diabetes (T1D) [37]
				LCMV infection [38]