FIGURE 2. SEPARABLE ANTIGEN-SPECIFIC T_FH AND B CELL LINEAGES.

We depict critical sets of molecular interactions at Checkpoint II that appear common to all antigen-specific effector T_FH interactions with antigen-primed pMHCII-expressing B cells. We propose that all sub-types of functionally distinct T_H cell lineages can also program the migration to the T-B borders and B cell zones to become T_FH cells and regulate B cell fate and function. Further, these separate effector T_FH lineages, depicted according to their original T_H cell program, will promote distinct B cell lineage decisions at Checkpoint II. We propose that antibody isotype is a major ‘lineage’ decision for antigen-specific B cells and that within each isotype-specific lineage the secondary outcomes of plasma cell versus GC B cell fate may be controlled by the duration of contact at Checkpoint II. Entry into the GC pathway involves clonal expansion, somatic BCR diversification and affinity-based selection for all isotype-specific GC B cells at Checkpoint IIIa. GC B cells with a positive selection ‘imprint’ at Checkpoint IIIa will form stable cognate interactions with pMHCII-specific GC T_FH cells at Checkpoint IIIb. We propose that there is some lineage maintenance between the effector T_FH and the GC T_FH creating distinct T_FH lineages dedicated to the regulation of separate isotype-specific B cells. In this model, IL-4 expressing GC T_FH will re-connect with IgG1⁺ GC B cells and IFN-γ+ T_FH will re-connect with IgG2a⁺ GC B cells as demonstrated by Locksley and colleagues [40**]. It is plausible that the duration of intercellular contact regulates memory B cell versus long-lived plasma cell fate and function at this point of memory B lineage development.