Follicular helper T cells as cognate regulators of B cell immunity
Introduction
Helper T cell regulated B cell immunity is considered the basis of long-term immune protection provided by most vaccines in use today. There are spatial and temporal constraints on cognate programming events following antigen-specific priming that serve as developmental checkpoints in clonal selection and the commitment to adaptive immune function [1, 2]. The rules that govern information exchange at each developmental checkpoint define the molecular mechanisms of antigen-specific immune protection in this pathway and are the focus of the current review.
Follicular helper T (TFH) cells are now recognized as the class of helper T cells that regulate the multiple stages of B cell immunity (Figure 1) [3, 4, 5, 6]. After initial contact with antigen-experienced DC (Checkpoint I), antigen-specific effector TFH cells emerge as CXCR5+CCR7− TH cells that migrate to the follicular regions of lymphoid organs to form stable contacts with antigen-primed B cells (Checkpoint II). Subsequent to cognate B cell contact, a cohort of effector TFH cells migrate to germinal centers, form stable contacts with variant GC B cells (Checkpoint III) to regulate the development of antigen-specific memory B cell compartment in ways that remain poorly understood. Finally, memory TFH cells persist within the priming environment to regulate the antigen-specific memory B cell response to rechallenge (Checkpoint IV). We propose that the strength of antigen receptor binding, the duration of cellular contact and the molecular context of cognate interactions are the defining attributes of each developmental checkpoint in vivo.
Section snippets
Initiating adaptive immunity: Checkpoint I
Vaccines provide foreign antigen within an inflammatory context to initiate dendritic cell (DC) maturation. Antigen-experienced DC will express peptide–MHC class II (pMHCII) complexes and a spectrum of secreted and surface-expressed molecules to recruit naive pMHCII-specific TH cells (Checkpoint Ia), promote TH clonal expansion and effector TH cell differentiation. The strength of TCR–pMHCII interactions and the extended molecular context of these cognate events impact antigen-specific TH cell
Pre-GC effector TFH cells: Checkpoint II
The cardinal feature of antigen-specific CXCR5+ TFH cells is migration toward the B cell zones of secondary lymphoid tissue [12, 13], and then, placement of an ongoing immune response within the GCs [14, 15]. Functional analysis in vitro [15], and then, in vivo upon adoptive transfer [16] established the propensity of the CXCR5+ TH compartment to support antibody production by B cells. The presence of antigen-specific TH cells within the GC has been described in human tonsils [17, 18] and
Effector TFH function: lineage and location
The spectrum of helper T cell functions with regulatory impact on different cellular targets is extensive and expanding [29•]. The programming and organization of these functions across different subtypes of effector TH cells is still an area of intense research. In this context, the assignment of cytokine production by effector TFH cell functions remains controversial. Early assessments of cytokine production by in vitro restimulated CXCR5+ TFH cells indicated IL-2, IFN-γ, and IL-10 from human
Germinal centers: Checkpoint III
The GC cycle of activity begins with recruitment and massive expansion of antigen-specific B cells in the B cell zones of secondary lymphoid tissue. There is evidence for BCR-affinity-based selection for entry into the GC cycle [43]. It is curious to speculate that the strength of pMHCII–TCR contact at Checkpoint II influences this developmental progression. In this model, the initial strength of BCR binding to antigen may be indirectly responsible for the duration of effector TFH cell pMHCII+
GC TFH function: separate B cell lineages
In their recent analysis of TFH–GC B cell doublets, Locksey and colleagues [40••] provided another surprising and potentially important insight into our understanding of GC–cognate interactions. These studies isolated doublets from day 21 of an immune response and demonstrated the phenotype of TFH cells and phenotype/genotype of antigen-specific GC B cells. Most remarkably, IL-4 producing TFH cells paired with IgG1 expressing GC B cells and IFN-γ producing TFH cells paired with IgG2a expressing
Memory B cell response: Checkpoint IV
CXCR5+ TH cells were first reported in the peripheral blood of humans [56] but were subsequently demonstrated to express reduced capacity to promote antibody production in vitro [31]. How these circulating CXCR5+ cells relate to the resident TFH compartment in peripheral LNs [4, 30•] has not been resolved. Our recent demonstration of a memory counterpart to the antigen-specific effector TFH population indicates a cohort of CXCR5+ TFH cells that persists locally to regulate accelerated memory B
Conclusions
TFH cells define a class of regulatory TH cells specialized for the cognate control of all stages of antigen-specific B cell development. Recent advances in this field indicate that initial contact with pMHCII-expressing DC induces multiple subtypes of CXCR5+ effector TFH cells producing different cytokines involved in the programming of B cell immunity. Antibody isotype switch is one major facet of the B cell response regulated by cognate control that may define antigen-specific B lineage
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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