Plexin B2 and Semaphorin 4C Guide T Cell Recruitment and Function in the Germinal Center

Abstract

Follicular T helper (T) cells orchestrate the germinal center (GC) response locally. T localization in GCs is controlled by chemo-guidance cues and antigen-specific adhesion. Here. we define an antigen-independent, contact-dependent, adhesive guidance system for T cells. Unusual for amoeboid cell migration, the system is composed of transmembrane plexin B2 (PlxnB2) molecule, which is highly expressed by GC B cells, and its transmembrane binding partner semaphorin 4C (Sema4C), which is upregulated on T cells. Sema4C on T cells serves as a receptor to sense the GC-presented PlxnB2 cue and biases T migration inwards at the GC edge to promote GC access. The absence of PlxnB2 from the GC or Sema4C from T cells causes T accumulation along the GC border, impairs T-B cell interactions in the GC, and is associated with defective plasma cell production and affinity maturation. Therefore, Sema4C and PlxnB2 regulate GC T recruitment and function and optimize antibody responses.

T follicular helper cell heterogeneity: Time, space, and function

“…GC B cells robustly express plexin B (PlxnB), which interacts with its binding partner semaphorin 4C (Sema4C) that is upregulated by GC Tfh cells. 68 This interaction promotes adhesion and entanglement between GC Tfh and B cells and is thought to guide Sema4C-expressing Tfh cells for retention in the PlxnB-rich GC. 68 In contrast, ephrin B1 (EFNB1) on GC B cells, signaling through Ephrin type-B receptor 6 (EPHB6) on the T cells, inhibits adhesion with GC Tfh cells, which in turn limit GC retention of Tfh cells.…”

“…GC B cells ro-bustly express plexin B (PlxnB), which interacts with its binding partner semaphorin 4C (Sema4C) that is upregulated by GC Tfh cells 68. GC B cells ro-bustly express plexin B (PlxnB), which interacts with its binding partner semaphorin 4C (Sema4C) that is upregulated by GC Tfh cells 68.…”

“…regulated by factors provided by surrounding B cells. This interaction promotes adhesion and entanglement between GC Tfh and B cells and is thought to guide Sema4C-expressing Tfh cells for retention in the PlxnB-rich GC 68. This interaction promotes adhesion and entanglement between GC Tfh and B cells and is thought to guide Sema4C-expressing Tfh cells for retention in the PlxnB-rich GC 68.…”

T cell interactions with B cells during germinal center formation, a three‐step model

“…138 In addition, Plexin B2 (PlxnB2) was found to be highly expressed in GC B cells in a T-cell-dependent manner together with other axon guidance genes, such as BASP1. 139,140 The PlxnB2 ligand, Sema4C is specifically expressed in Tfh cells and increased surface expression resulted in effective positioning of Tfh cells in the GC.…”

“…These findings suggest that the Sema4C:PlxnB2 interactions might potentiate TCR signaling and integrin-mediated adhesion at the T-B synapse. 140 In addition to positive mechanisms evolved to prolong T-cell in- Ephrin-B1. 141,142 In a cytometry based cell-cell conjugate assay, it was demonstrated that T-cell interactions with highly Ephrin-B1expressing B cells was reduced compared to non-transduced control cells, in an antigen-specific manner.…”