Abstract
T follicular helper (Tfh) cells participate in humoral immune by promoting inflammation and aiding B cells survival, proliferation, maturation, and generation autoantibodies. The plasticity of Tfh cells enables the immune system to adjust the direction of differentiation according to the degree of the immune response, regulate the germinal center (GC) response and maintain homeostasis. Tfh differentiation involves several signaling factors, including multiple cytokines, receptors, transcription factors and genes. The signal transducer and activator of transcription (STAT) family signaling pathways are crucial for Tfh formation. However, because of the multi-factorial and multi-stage features of Tfh differentiation, every STAT member plays a role in Tfh differentiation, but is not completely depended on. With the gradual recognition of different Tfh subsets (Tfh1, Tfh2, Tfh17), the process of Tfh differentiation can no longer be explained by straight-line derivation models. In this review, we summarize the roles of different STATs in mediating Tfh subsets, analyze the contributions of mutual restraint and cooperation among cytokine-STAT signals to terminal Tfh differentiation, and clarify the multi-source pathways of Tfh differentiation with a three-dimensional illustration.
Highlights
Antibody production is reliant upon the formation of germinal center (GC) in secondary lymphoid organs, where B cells undergo proliferation, differentiation, and somatic hypermutation aimed at producing high affinity antibodies
Research has demonstrated that transforming growth factor b (TGF-b) plus IL-12/IL-23 was the most effective in up-regulating the expression of CXCR5, B-cell lymphoma 6 (Bcl-6) and IL21, while other STAT3-activating cytokines synergistically enhanced T follicular helper (Tfh) differentiation [22]
At the early stage of differentiation, environmental signals are indispensable in conferring the heterogeneity of Tfh phenotypes
Summary
Antibody production is reliant upon the formation of GCs in secondary lymphoid organs, where B cells undergo proliferation, differentiation, and somatic hypermutation aimed at producing high affinity antibodies. The Tfh1 differentiation pathway can be initiated by type 1 responses in which STAT1/4-activating cytokines expand, such as viral infection, vaccination, or some autoimmune diseases [9, 10, 12, 13]. Surface receptors, and transcription factors, are crucial regulators of Tfh differentiation at every stage.
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