Date of Award
Medical Doctor (MD)
Follicular helper T (TFH) cells are a specialized subset of CD4+ T cells essential for the affinity-based selection of B cells in the germinal center (GC). However, it remains unclear how transient entanglement between TFH and GC B cells lead to selective B cell proliferation and differential somatic hypermutation, especially given the evidence that BCR signaling is closely guarded by phosphatases within the GC. Here we present a model involving the interaction between SEMA4D on TFH cells and CD72 on GC B cells. We found that as the GC response progressed during acute murine lymphocytic choriomeningitis virus infection, TFH cells temporally downregulated surface expression of SEMA4D, accompanied by increased CD40L expression and decreased IFNγ and IL-21 production. Different levels of SEMA4D expression on TFH cells correlated with significantly varied phosphorylation levels of B cell receptor signaling cascade molecules Syk, Btk, BLNK, and tyrosine kinases as a whole. Such variations in B cell receptor signaling in GC B cells affected their proliferation, localization, and somatic hypermutation. Therefore, TFH cells utilize SEMA4D and its temporal down-regulation to regulate affinity maturation and fine-tune selective pressure over GC B cells over the course of the GC response.
Li, Ningcheng, "Down-Regulation Of Sema4d On Follicular T Helper Cell Fine-Tunes Germinal Center B Cell Response" (2017). Yale Medicine Thesis Digital Library. 2146.