Regulation Of The Germinal Center Reaction By Plexin B2 And Semaphorin 4C Molecules

Lymphocyte migration and positioning in secondary lymphoid organs are predominantly orchestrated by soluble guidance cues in the form of chemo-attractants or repellents,while contact-dependent guidance including integrin-mediated adhesion generally is not required.Proper recruitment of follicular helper T(TFH)cells to the germinal center(GC)are crucial for antibody affinity maturation and productive humoral immunity.The plexin family of receptors and semaphorin family of ligands play important roles in repulsive guidance of neuronal migration.Here we report that proper GC positioning of TFH cells is controlled by the plexin B2(PlxnB2)molecule,which is highly expressed by GC B cells,and by its high-affinity ligand semaphorin 4C(Sema4C),which is uniquely upregulated on TFH cells.As opposed to effectuating repulsion to plexin-expressing cells,a scenario typically seen in the context of nervous and cardiovascular development,Sema4 C serves as an adhesionbased guidance receptor for TFH cells to penetrate the GC territory represented by the PlxnB2-expressing B-cell ensemble.The absence of either PlxnB2 from the GC ensemble or Sema4 C from T cells causes T-cell mislocalization at the GC border.This lack of GC penetration is associated with an altered TFH maintenance program,reduction in plasma cell output and impaired affinity maturation.T-B cells conjugation can be enhanced when overexpress PlxnB2 and Sema4 C in B cells and T cells,respectly.And this conjugation is independent on LFA.T-cell mislocalization caused by the deficiency of PlxnB2 is not due to the expression of chemokine receptors,indicated that PlxnB2 and Sema4 C constitute a new contact-dependent guidance system.Sema4 D as another potential ligand of PlxnB2,does not involve the GC reactions,means that Sema4 D is not the ligand of PlxnB2 in GC B cells.Therefore,PlxnB2 and Sema4 C constitute a novel contact-dependent guidance system that precision-regulates TFH cell migration and positioning to support efficient GC reactions.These results improve our understanding humoral immune regulation.