Regulators of Tfh Cell Differentiation

Abstract

The follicular helper T (Tfh) cells help is critical for activation of B cells, antibody class switching, and germinal center (GC) formation. The Tfh cells are characterized by the expression of CXC chemokine receptor 5 (CXCR5), ICOS, programed death 1 (PD-1), B cell lymphoma 6 (BCL-6), and IL-21. They are involved in clearing infections and are adversely linked with autoimmune diseases and also have a role in viral replication as well as clearance. On the one hand, Tfh cells are generated from naive CD4+ T cells with sequential steps involving cytokine signaling (IL-21, IL-6, IL-12, activin A), migration, and positioning in the GC by CXCR5, surface receptors (ICOS/ICOSL, signaling lymphocyte activation molecule-associated protein/signaling lymphocyte activation molecule) as well as transcription factor (BCL-6, c-Maf, and signal transducer and activator of transcription 3) signaling and repressor miR155. On the other hand, Tfh generation is negatively regulated at specific steps of Tfh generation by specific cytokine (IL-2, IL-7), surface receptor (PD-1, CTLA-4), transcription factors B lymphocyte maturation protein 1, signal transducer and activator of transcription 5, T-bet, KLF-2 signaling, and repressor miR 146a. Interestingly, miR-17–92 and FOXO1 act as a positive as well as a negative regulator of Tfh differentiation depending on the time of expression and disease specificity. Tfh cells are also generated from the conversion of other effector T cells as exemplified by Th1 cells converting into Tfh during viral infection. The mechanistic details of effector T cells conversion into Tfh are yet to be clear. To manipulate Tfh cells for therapeutic implication and or for effective vaccination strategies, it is important to know positive and negative regulators of Tfh generation. Hence, in this review, we have highlighted and interlinked molecular signaling from cytokines, surface receptors, transcription factors, ubiquitin ligase, and microRNA as positive and negative regulators for Tfh differentiation.

The Emerging Role of Epigenetics in Autoimmune Thyroid Diseases

“…Increased circulating Th17 cells have been found in AITD patients, and IL-17 has also been identified as an important cytokine in the pathogenesis of AITD (25, 32–34, 36). Tfh cells are characterized by the expression of CXC chemokine receptor 5 (CXCR5) and the production of IL-21 and are critical for the activation of B cells and germinal center formation (37). Th22 cells are characterized by the transcription factor of aryl hydrocarbon receptor and the production of IL-22 (38).…”

Biological Omics Analysis of Tumor Mutation Burden Combined with Immune Infiltrates in Uterine Corpus Endometrial Carcinoma

“…Memory CD4 T cells help the body obtain long-term protection against pathogen reinfection (40). Tfh cells secrete BCL-6, IL-21, CXCR5, and ICOS, which are mainly involved in the information transmission during B cell differentiation, helping to activate B cells and maintain humoral immune response for a long time (41,42). Macrophages participate in the tumor immune response through different polarization methods: classic M1 macrophages produce IL-12 and promote tumor immune response: while M2 macrophages produce IL-10 to promote tumor progression (43).…”

Di-(2-ethylhexyl)-phthalate interferes with T-follicular helper cell differentiation and cytokine secretion through signaling lymphocytic activation molecule family member-1

“…T fh cells synthesize characteristic cytokines (such as interleukin [IL]-21 and IL-4) that facilitate antibody production by and class-switch recombination events in B-cells. Over recent years, it has been shown that the expression of typical transcription factors (such as Bcl-6 and c-MAF)along with their mutual regulationis of crucial significance for the initial differentiation of, and essential functions thereafter, of T fh cells (Crotty 2014;Qi et al 2014;Butler and Kulu 2015;Jogdand et al 2016;Wali et al 2016;Qin et al 2018).…”