The origins, function, and regulation of T follicular helper cells

Abstract

The generation of high-affinity antibodies (Abs) plays a critical role in the neutralization and clearance of pathogens and subsequent host survival after natural infection with a variety of microorganisms. Most currently available vaccines rely on the induction of long-lived protective humoral immune responses by memory B cells and plasma cells, underscoring the importance of Abs in host protection. Ab responses against most antigens (Ags) require interactions between B cells and CD4(+) T helper cells, and it is now well recognized that T follicular helper cells (Tfh) specialize in providing cognate help to B cells and are fundamentally required for the generation of T cell-dependent B cell responses. Perturbations in the development and/or function of Tfh cells can manifest as immunopathologies, such as immunodeficiency, autoimmunity, and malignancy. Unraveling the cellular and molecular requirements underlying Tfh cell formation and maintenance will help to identify molecules that could be targeted for the treatment of immunological diseases that are characterized by insufficient or excessive Ab responses.

Figure 1.

Anatomical localization and cellular requirements for Tfh cell generation. (A; i) Naive CD4⁺ T cells are activated in interfollicular areas or T cell zones of lymphoid tissues after recognition of peptide–MHC class II complexes on DCs. (i) DCs provide signals that up-regulate CXCR5 and down-regulate CCR7 on CD4⁺ T cells allowing them to migrate to B cell follicles. (ii) At the T cell–B cell border, pre–Tfh cells interact with activated B cells presenting cognate Ag. This results in the pre–Tfh cells delivering help to the B cells, resulting in their differentiation into short-lived extrafollicular plasmablasts or their migration into follicles to form GCs. Ongoing stimulation and Ag presentation provided by B cells drives the full development of Tfh cells. (iii) Within GC, Tfh cells continue to provide help to the B cells, supporting the GC reaction and facilitating the generation of long-lived plasma cells and memory B cells. Reciprocal signals provided by the B cells are also crucial for sustaining the Tfh cells. (B) Initial priming of naive CD4⁺ T cells by DCs induces expression of Bcl-6 and CXCR5; this requires ICOS/ICOS-L interactions. DCs may produce IL-6 and IL-27, which promote Bcl-6 and c-Maf expression, as well as IL-21 production by CD4⁺ T cells, in a STAT3-dependent fashion. CXCR5-mediated relocation of Bcl-6⁺CXCR5⁺ pre–Tfh cells to the T cell–B cell border allows subsequent interactions with Ag-specific B cells. The Tfh program is imprinted after subsequent interactions with B cells in the GC. The interactions are dependent on the formation of stable T cell–B cell conjugates, which requires CD4⁺ T cell–intrinsic signaling via SAP-associating receptors (CD84) and involves CD40L/CD40, ICOS/ICOS-L, and CD28/CD86. IL-21 produced by Tfh cells can act in an autocrine manner to maintain Tfh cells at various stages of differentiation. Similarly, B cell–derived IL-6, and possibly IL-27, could contribute to the maintenance of Tfh cells. Tfh cells mediate differentiation of GC B cells into memory and plasma cells via the provision of CD40L and IL-21.

Figure 2.

Molecular regulation of Tfh development. Tfh development requires the integrated and balanced function of numerous transcription factors. BATF acts proximally by inducing Bcl-6 and c-Maf. Bcl-6 imprints a Tfh fate by suppressing expression and/or function of transcriptional regulators of alternate effector fates (i.e., Tbx21 [Th1], Gata3 [Th2], and Rorc [Th17]), microRNAs that suppress Tfh generation, and Prdm1 (encoding Blimp-1), which directly suppresses Bcl-6. c-Maf contributes to Tfh cells by inducing CXCR5 and IL-21. STAT3-activating cytokines IL-6, IL-21, and IL-27 can also induce c-Maf, and STAT3 can directly induce IL-21. IL-12 induces IL-21 in a STAT3-dependent manner, but it is unknown whether this involves c-Maf or is a direct effect of STAT3. Tfh generation is restricted by Blimp-1, which is induced by IL-2 in a STAT5-dependent manner and blocks Bcl-6 expression, and by T-bet (induced by IL-12), which physically associates with Bcl-6 and prevents Bcl-6–dependent repression.

Figure 3.

CD4⁺ T cell flexibility. Naive CD4⁺ T cells interacting with Ag-presenting DCs can acquire expression of Bcl-6. However, their commitment to specific effector lineages is governed by additional signals and the coordinated and antagonistic actions of different transcription factors. Sufficient levels of T-bet or GATA3, or potentially RORγt, will override the repressive effect of Bcl-6 to yield Th1, Th2, or Th17 cells, respectively. Yet some DC-primed naive CD4⁺ T cells will become pre–Tfh cells, defined by CXCR5 and Bcl-6 expression, which differentiate into GC Tfh cells after interactions with cognate B cells. Th1, Th2, and, presumably, Th17 cells retain flexibility in their differentiation programs such that under conditions of sustained Ag (e.g., persistent pathogen infection) they can down-regulate T-bet, Gata3, or RORγt, up-regulate Bcl6, and convert to Tfh cells. Regardless of their origin, Tfh cells drive the differentiation of cognate B cells into memory and plasma cells, which is necessary for long-lived protective Ab responses. The magnitude of Tfh-induced humoral responses is regulated by thymic-derived follicular T reg cells. Although pre–Th1, pre–Th2, pre–Th17, and pre–Tfh cells are illustrated as individual cell types, it is equally possible that Th1, Th2, Th17, and Tfh cells arise from a common CD4⁺ T cell precursor that acquires expression of T-bet, GATA3, RORγt, and Bcl-6, and then differentiates into bona fide effector cells after delivery of appropriate instructive cues. The scheme outlined for Th17 cells differentiating into Tfh cells is speculative. Although Th17 cells shares features with Tfh cells, it is unknown whether this reflects an intrinsic characteristic of Th17 cells or their conversion to Tfh cells.