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

Establishment of effective immunity against invading microbes depends on continuous generation of antibodies that facilitate pathogen clearance. Long-lived plasma cells with the capacity to produce high affinity antibodies evolve in germinal centers (GCs), where B cells undergo somatic hypermutation and are subjected to affinity-based selection. Here, we focus on the cellular interactions that take place early in the antibody immune response during GC colonization. Clones bearing B-cell receptors with different affinities and specificities compete for entry to the GC, at the boundary between the B-cell and T-cell zones in lymphoid organs. During this process, B cells compete for interactions with T follicular helper cells, which provide selection signals required for differentiation into GC cells and antibody secreting cells. These cellular engagements are long-lasting and depend on activation of adhesion molecules that support persistent interactions and promote transmission of signals between the cells. Here, we discuss how interactions between cognate T and B cells are primarily maintained by three types of molecular interactions: homophilic signaling lymphocytic activation molecule (SLAM) interactions, T-cell receptor: peptide-loaded major histocompatibility class II (pMHCII), and LFA-1:ICAMs. These essential components support a three-step process that controls clonal selection for entry into the antibody affinity maturation response in the GC, and establishment of long-lasting antibody-mediated immunity.