Abstract
Helping B cells and antibody responses is a major function of CD4+T helper cells. Follicular helper T (Tfh) cells are identified as a subset of CD4+T helper cells, which is specialized in helping B cells in the germinal center reaction. Tfh cells express high levels of CXCR5, PD-1, IL-21, and other characteristic markers. Accumulating evidence has demonstrated that the dysregulation of Tfh cells is involved in infectious, inflammatory, and autoimmune diseases, including lymphocytic choriomeningitis virus (LCMV) infection, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), IgG4-related disease (IgG4-RD), Sjögren syndrome (SS), and type 1 diabetes (T1D). Activation of subset-specific transcription factors is the essential step for Tfh cell differentiation. The differentiation of Tfh cells is regulated by a complicated network of transcription factors, including positive factors (Bcl6, ATF-3, Batf, IRF4, c-Maf, and so on) and negative factors (Blimp-1, STAT5, IRF8, Bach2, and so on). The current knowledge underlying the molecular mechanisms of Tfh cell differentiation at the transcriptional level is summarized in this paper, which will provide many perspectives to explore the pathogenesis and treatment of the relevant immune diseases.
Highlights
CD4+helper T cells play a critical role in forming and amplifying the abilities of the immune system
Once naïve CD4+T cells are activated by antigen-presenting cells (APCs) together with IL-6 and IL-21, they will differentiate into Tfh cells
Many questions remain to be further investigated. (i) Are there other Tfh-specific transcription factors beyond the abovementioned factors? (ii) How do Tfh-specific transcriptional factors impact epigenetic mechanisms during inducing Tfh cell generation? (iii) What are the factors’ stage-specific requirements? (iv) What are the molecular mechanisms contributing to Tfh cell maintenance and memory formation?
Summary
CD4+helper T cells play a critical role in forming and amplifying the abilities of the immune system. Tfh cells are characterized by high expression of the chemokine receptor CXCR5, the transcription factor Bcl, the costimulatory molecule ICOS, and the coinhibitory molecule PD-1. During the initiation phase of Tfh cell differentiation, multiple signals take part in the process, including transcription factors (Bcl, Ascl, Batf, IRF4, c-Maf, and so on), costimulatory molecule(ICOS), and cytokines(IL-6/IL-21); in particular, higher TCR affinity is necessary for initiation of Tfh cell. Bcl6+CXCR5+ Tfh precursor cells move into the T-B border zone, where they accept other differentiation signals from activated B cells [8]. After this appointment, the toughened expression of Bcl regulates surface markers, which accelerates the migration of Tfh cells into GC, where they offer assistant signals for B cells [9, 10] (Figure 1). The knowledge of the transcriptional mechanism underlying Tfh cell differentiation will be comprehensively described in this paper, which will highlight the possible future directions
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