Follicular helper T cells as cognate regulators of B cell immunity

Abstract

Follicular helper T (T(FH)) cells are a class of helper T cells specialized in the cognate control of antigen-specific B cell immunity. Upon first contact with antigen-primed B cells, pregerminal center effector T(FH) cells promote B cell clonal expansion, antibody isotype switch, plasma cell differentiation, and the induction of germinal centers. By contrast, within germinal centers, T(FH) cells regulate the fate of antigen-specific GC B cells expressing high-affinity variant B cell receptors to promote memory B cell and long-lived plasma cell development. Recent studies unravel multiple signals controlling T(FH) development and functional subtypes of antigen-specific T(FH) cells, including memory T(FH) cells that accelerate memory B cell responses to antigen rechallenge in vivo.

FIGURE 1. COGNATE TH CELL REGULATION OF B CELL IMMUNITY

Following local protein vaccination, mature antigen-experienced dendritic cells from the site of injection traffic to the draining lymphoid tissue to prime pMHCII-specific naive T_H cells at Checkpoint Ia. Antigen can also be transported to the subcapsullar sinus by macrophage to present native cell associate antigen to B cells at Checkpoint Ib. Antigen-specific B cells will take up protein antigen, process and present pMHCII complexes and move towards the T-B borders to interact with pMHCII-specific effector T_FH cells at Checkpoint II. Following stable cognate contact a cohort of antigen-specific B cells will move into the follicular regions, massively expand to form secondary follicles, somatically diversify their BCR, express the variant BCR and then traverse FDC networks in the light zone of germinal center at continuous Checkpoint IIIa interactions. GC B cells expressing high affinity variant BCR form stable contacts with GC T_FH cells at Checkpoint IIIb prior to GC exit and entry into the memory B cell compartment as either memory response precursors or long-lived plasma cells. Antigen-specific memory T_FH cells and memory B cells persist in the priming lymphoid tissue to interact upon secondary challenge with antigen at Checkpoint IV a requisite regulatory interaction for expansion of memory B cells and formation of memory response plasma cells.

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.