T follicular helper cell differentiation, function, and roles in disease

Abstract

Follicular helper T (Tfh) cells are specialized providers of T cell help to B cells, and are essential for germinal center formation, affinity maturation, and the development of most high-affinity antibodies and memory B cells. Tfh cell differentiation is a multistage, multifactorial process involving B cell lymphoma 6 (Bcl6) and other transcription factors. This article reviews understanding of Tfh cell biology, including their differentiation, migration, transcriptional regulation, and B cell help functions. Tfh cells are critical components of many protective immune responses against pathogens. As such, there is strong interest in harnessing Tfh cells to improve vaccination strategies. Tfh cells also have roles in a range of other diseases, particularly autoimmune diseases. Overall, there have been dramatic advances in this young field, but there is much to be learned about Tfh cell biology in the interest of applying that knowledge to biomedical needs.

Figure 1. Overview of Tfh cell differentiation

(a) Stages of Tfh cell differentiation, highlighting roles of migration-associated molecules. (b) Signals in CD4 T cell differentiation. A simplified model of CD4 T cell differentiation pathways, showing transcription factors and inducing factors, highlighting apparent differences between human and mouse Tfh cell differentiation.

Figure 2. Tfh cell memory development

Memory Tfh cells develop over time and appear to develop from either Tfh cells or GC Tfh cells. Memory Tfh cells exhibit phenotypic heterogeneity. Memory Tfh cells that retain stable expression of low amounts of PD-1 (PD-1^lo or PD-1⁺) are more polarized and highly functional memory Tfh cells, when compared to PD-1^neg memory Tfh cells. Upon reactivation, memory Tfh cells predominantly become Tfh cells and can go on to become GC Tfh cells, although some memory Tfh cells can go on to become non-Tfh cells in a recall response.

Figure 3. Bcl6 protein domain structure and interacting proteins

The functional domains of Bcl6 are shown with regions of interest indicated. Bcl6 interacting proteins are also shown with the Bcl6 regions with which they interact, if known. Numbers indicate amino acid positions of human Bcl6. Bcl6 is shown in blue. ‘BTB’ is the broad-complex, tramtrack, and bric-à-brac domain. Bcl6 self dimerizes via the BTB domain, but the self-dimerization is not shown, for simplicity. ‘HDAC’, histone deacetylase complex. ‘Ub’, ubiquitin. ‘PEST’ indicates a PEST (proline, glutamic acid, serine, threonine-rich) ubiquitination domain (1 and 2) in Bcl6. Ⓟ symbolizes phosphorylation. Ac symbolizes acetylation, and the acetylation is mediated by p300. The Zn fingers are numbered 1–6 (‘Zn1’). NuRD, nucleosome-remodeling and histone deacetylation complex.

Figure 4. An architectural blueprint conceptual model of CD4 T⁺ cell differentiation programs

(a) Regulation of Tfh differentiation by Bcl6 and cooperating Tfh transcription factors (‘TFs’). Tfh cell biology can be divided into four categories, indicated in different colors, with representative genes shown for each category. All differentiation and product genes shown are upregulated in Tfh cells. All alternative fates genes shown are downregulated, and are grouped in subcategories (Th1, Th2, IL-2 and Blimp1, Th17, and forkhead box gene regulation). Genes in the location category include genes that are upregulated (+) or downregulated (−). (b) An architectural blueprint model of Tfh cell differentiation and how it relates to other CD4⁺ T cell differentiation programs, within a single cell. The Tfh cell differentiation program (shown in 4a) is projected as a flat plane, as if it were the architectural blueprint for a floor of a multistory building, but in this case it is the blueprint within a CD4⁺ T cell instead of a building. The Th1 cell program is projected as the blueprint of another floor. Bcl6 prevents activity of the Th1 cell program in a Tfh cell by blocking the expression of genes central to the Th1 cell blueprint. Extracellular signals can enter as inputs from the surface of the cell, such as through IL2R or IFNγR, shown at the edge of the Th1 level. Proteins whose genes are inhibited by Bcl6 are indicated by a red —|. The Th17 cell program is projected as another blueprint, which is also inhibited by Bcl6. The Th2 and Treg cell programs are not shown due to space constraints but are conceptually analogous to the Th1 and Th17 cell program blueprints.