Follicular helper T cells: lineage and location

Abstract

Follicular helper T (Tfh) cells are the class of effector T helper cells that regulates the step-wise development of antigen-specific B cell immunity in vivo. Deployment of CXCR5+ Tfh cells to B cell zones of lymphoid tissues and stable cognate interactions with B cells are central to the delivery of antigen-specific Tfh cell function. Here, we review recent advances that have helped to unravel distinctive elements of developmental programming for Tfh cells and unique effector Tfh cell functions focused on antigen-primed B cells. Understanding the regulatory functions of Tfh cells in the germinal center and the subsequent regulation of memory B cell responses to antigen recall represent the frontiers of this research area with the potential to alter fundamentally the design of future vaccines.

Figure 1. T_H Lineage Commitment and Micro-environmental Location

This figure depicted the first contact between pMHCII⁺ DC and naive pMHCII-specific T_H cells (referred to as Checkpoint 1A). Intercellular cognate contact involves TCR-pMHCII interactions in the context of a range of co-stimulatory that include CD80/86 and CD28 interactions. The extent and quality of co-stimulation will be controlled by the inflammatory context of antigen exposure for the DC at immunization. The cytokines produced by the activated DC as well as the initial cytokines produced by the activated T_H cells will regulate the T_H cell lineage that develops after clonal selection, expansion and differentiation in effector function. Some of the major known influences to the developmental of separate T_H cell lineages are depicted to contrast to what is currently understood about effector T_FH development. The arc on the right depicts a time-point after clonal expansion and effector T_H cell differentiation when T_H cells from all lineages either 1) remain in the T cell areas of LNs or 2) migrate to the B cell areas or 3) leave the LNs to distal tissues and not return during the first week after priming. The migratory division and cell surface phenotype are predictions based on our recent study using protein vaccination in an adjuvant containing a TLR-4 agonist and the use of an FTY720 analog to block LN emigration after priming (Fazilleau et al., 2009).

Figure 2. Delivery of Cognate Effector T_FH function to pMHCII-expressing B cells

The main focus of this display are the molecular interactions known to be involved at the cellular interface upon first contact of an effector T_FH cell and an antigen-primed B cells. Cell surface molecules are emphasized with the presence of IL-21 depicted as one of many cytokine exchanges that may ensue. On the left hand side of the figure, we depict multiple T_FH cell subsets that would arise as T_H cells of known lineages that adopt the developmental program of follicular placement. This program is largely defined as the loss of CCR7 and expression of CXCR5 but relies on appropriate positioning in the follicular regions and subsequent contact with an antigen-primed B cell. ON the riight hand side of the figure, we depict the two major outcomes for B cells after receipt of antigen-specific T cell help: 1) Entry into the extra-follicular short-lived PC pathway to terminal differentiation or 2) movement into the follicular areas to rapidly expand and form the GC in the pathway to memory B cell development. Isotype switch proceeds in both pathways controlled by the cytokine mixture and cell contact received at this critical second developmental checkpoint.

Figure 3. Selection of GC B cells and the cognate control of GC B cell

The left side of this figure depicts the molecular interactions associated with continuous movement of variant GC B cells along the stromal network of mature FDC that have coated immune complexes on their dense light zone processes through FcR and complement receptors. The right side of the figure depicts the intercellular engagement of a GC T_FH cell and a GC B cell. We have not labeled the molecules as there is still very little information on the molecular nature of this interaction regarding cell surface molecules or secreted cytokines. The phenotype that has been reported is largely similar between effector T_FH cells and their GC T_FH counterparts. The far right of figure depicts the predicted cellular outcomes of Checkpoint IIIA and IIIB interactions based on the known output of the GC reaction. There are broadly two classes of memory B cell that exits the GC 1) high affinity precursors for the memory response to antigen re-challenge that exist in a variety of physiological states and 2) long-lived PCs that contribute high affinity antibodies to the circulation of the animal largely for life. The latter compratment is not considered able to react to antigen re-challenge but is nevertheless considered a component of long-term B immunity. Finally, each post-GC pathway potentially comprises of all antibody isotypes that we propose may be considered to be separable lineages of memory B cells. For example, it is likely that IgG1 memory B cells have diverged in development from IgA memory B cells and not only received distinct inducing signals to develop in the first place (at Checkpoint II), but reside in separable microenvironmental niches around the body with distinguishable migratory phenotype, but also require unique activation requirements upon antigen re-challenge.