The good, the bad and the ugly — TFH cells in human health and disease

Key Points

  • Naive CD4+ T cells have the potential to differentiate into specialized effector cell populations that have distinct functions during infection; T follicular helper (TFH) cells are the effector CD4+ T cell population responsible for mediating the activation and differentiation of B cells to generate protective humoral (antibody-based) immunity.

  • TFH cells are defined as CD4+ T cells that migrate to follicles and interact with antigen-specific B cells to support their differentiation into memory or plasma cells. They can be identified from other CD4+ T cells on the basis of their unique surface phenotype, as they express the highest levels of CXC-chemokine receptor 5 (CXCR5), together with the surface receptors inducible T cell co-stimulator (ICOS) and programmed cell death protein 1 (PD1), the transcriptional repressor B cell lymphoma 6 (BCL-6) and the cytokine interleukin-21 (IL-21).They also lack expression of CC-chemokine receptor 7 (CCR7) and IL-7 receptor-α (IL-7Rα), and are hence defined as CD4+CXCR5hiPD1hiICOShiBCl-6+IL-21+CCR7IL-7Rα cells.

  • TFH cell differentiation is dependent on interactions with antigen-presenting dendritic cells and B cells that are mediated through specific receptor–ligand pairs, including cytokines and their receptors. Collectively, these signals induce the expression of a range of transcription factors that induce the differentiation of the activated CD4+ T cell to a TFH cell fate. Many molecules have been found to regulate TFH cell formation, including: CD28, ICOS, CD40 ligand (CD40L) and SLAM-associated protein (SAP)-associated receptors; signal transducer and activator of transcription 3 (STAT3)-activating cytokines IL-6 and IL-21 (particularly in combination); and BCL-6, MAF, basic leucine zipper transcriptional factor ATF-like (BATF) and interferon-regulatory factor 4.

  • Although originally identified as cells that are important for controlling responses to conventional T cell-dependent antigens, additional subsets of TFH cells have now been characterized, such as natural killer TFH cells and γδ TFH cells, which presumably contribute to immune responses against lipid, glycolipid and phosphopeptide antigens. Moreover, a distinct subset of regulatory T (TReg) cells — follicular TReg cells — seem to co-evolve with TFH cells and to restrain TFH cell function.

  • TFH cells are associated with numerous immunopathologies that are characterized by aberrant humoral immune responses. These include primary and acquired immunodeficiencies, systemic and organ-specific autoimmune diseases and T cell malignancies. Thus, targeting the pathways that are important for TFH cell formation in an attempt to either attenuate or enhance their function represents an attractive novel therapeutic strategy to treat these conditions.

Abstract

Antibody production is an important feature of the vertebrate immune system. Antibodies neutralize and clear pathogens, thereby protecting against infectious diseases. Such humoral immunity has great longevity, often persisting for the host's lifetime. Long-lived humoral immunity depends on help provided by CD4+ T cells, namely T follicular helper (TFH) cells, which support the differentiation of antigen-specific B cells into memory and plasma cells. TFH cells are stringently regulated, as aberrant TFH cell activity is involved in immunopathologies such as autoimmunity, immunodeficiencies and lymphomas. The elucidation of the mechanisms that regulate TFH cell differentiation, function and fate should highlight targets for novel therapeutics.

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Figure 1: Cellular and molecular regulation of TFH cell formation.
Figure 2: TFH cell subsets with specialized effector functions.

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Acknowledgements

Studies in the authors' laboratories into T follicular helper cells are supported by grants and fellowships that have been awarded by the National Health and Medical Research Council of Australia. The authors thank S. Crotty and H. Ueno for providing papers before publication.

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Correspondence to Stuart G. Tangye.

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Effects of gene deficiency on TFH cell formation (PDF 280 kb)

Glossary

Germinal centres

The structures that are formed by the expansion of antigen-activated B cell blasts that have migrated into the follicles of lymph nodes. The B cells in these structures proliferate and the immunoglobulin genes undergo somatic hypermutation before the cells leave as plasma cells or memory cells.

B cell lymphoma 6

(BCL-6). A transcriptional repressor identified as being crucial for the formation of T follicular helper (TFH) cells. Several mechanisms have been proposed for the role of BCL-6 in TFH cell commitment, including suppression of the expression of transcription factors that are required for the generation of alternative TH fates, suppression of microRNAs and cooperation with other transcriptional regulators to induce the expression of important TFH cell-related genes.

X-linked lymphoproliferative disease

A rare, often fatal, primary immunodeficiency disease that is characterized by an inability to mount an effective immune response against Epstein–Barr virus, as well as a susceptibility to developing lymphoma and/or hypogammaglobulinaemia.

SH2 domain-containing protein tyrosine phosphatase 1

(SHP1). A protein tyrosine phosphatase that is involved in suppressing intracellular signals delivered via numerous activating receptors, including T cell and B cell antigen receptors, as well as members of the signalling lymphocytic activation molecule (SLAM) family of surface receptors. One proposed mechanism of action is the direct or indirect dephosphorylation of components of the T cell receptor signalling pathway, such as CD3ζ, LCK, ζ-chain-associated protein kinase of 70 kDa (ZAP70) and phosphoinositide 3-kinase.

Follicular T regulatory cells

A subset of T regulatory (TReg) cells that co-opts the transcriptional machinery of T follicular helper (TFH) cells to facilitate their migration to germinal centres, where they can appropriately restrain humoral immune responses, thereby potentially preventing overzealous antibody responses. Follicular TReg cells can be identified by the expression of typical TFH cell surface markers (CXC-chemokine receptor 5 (CXCR5), inducible T cell co-stimulator (ICOS) and programmed cell death protein 1 (PD1)) along with the TReg transcription factor forkhead box P3. Their mechanism of action remains to be completely elucidated.

Follicular dendritic cells

Specialized non-haematopoietic stromal cells that reside in lymphoid follicles and germinal centres. These cells possess long dendrites and carry intact antigen on their surface. They are crucial for the optimal selection of B cells that produce antigen-binding antibodies.

γδ T cells

T cells that express the γδ T cell receptor. These T cells are present in the skin, vagina and intestinal epithelium as intraepithelial lymphocytes. Although the exact function of γδ T cells is unknown, it has been suggested that mucosal γδ T cells are involved in innate immune responses.

Sjögren's syndrome

A systemic autoimmune disease in which autoantibodies target and destroy exocrine glands such as the tear ducts and the salivary glands.

Systemic lupus erythematosus

(SLE). An autoimmune disease in which autoantibodies that are specific for DNA, RNA or proteins associated with nucleic acids form immune complexes. These complexes damage small blood vessels, especially in the kidneys. Patients with SLE generally have abnormal B and T cell function.

Myasthenia gravis

A chronic autoimmune disease that involves the generation of T cell-dependent autoantibodies that are specific for the acetylcholine receptor. These antibodies interfere with the transmission of signals at neuromuscular junctions.

Rheumatoid arthritis

An immunological disorder that is characterized by symmetrical polyarthritis, often progressing to crippling deformation after years of synovitis. It is associated with systemic immune activation and the presence of acute-phase reactants in the peripheral blood, as well as rheumatoid factor (immunoglobulins that are specific for IgG), which forms immune complexes that are deposited in many tissues.

Graves' disease

A type of autoimmune disease, and the most common form of hyperthyroidism in humans. It results from activating antibodies that are specific for the thyroid stimulating hormone receptor (TSHR). In mouse models of Graves' thyroiditis, the disease is induced by immunization with the TSHR.

Hashimoto's thyroiditis

An autoimmune disease in which self-reactive B cells and T cells target the thyroid, resulting in hypothyroidism.

Juvenile dermatomyositis

A chronic, multisystem autoimmune and inflammatory disease involving muscle, skin, blood vessels, the gastrointestinal tract and other organs. Autoantibodies are often detected in these patients, but their specificities have not yet been completely defined.

Isocitrate dehydrogenase 2

(IDH2). An enzyme that catalyses the oxidative decarboxylation of isocitrate to 2-oxoglutarate and is a component of the tricarboxylic acid cycle. Mutations in IDH1 and IDH3 have been detected in glioma, glioblastomas and acute myeloid leukaemia.

TET2

The TET2 gene encodes an oxygenase that catalyses the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine to alter the epigenetic status of DNA. It is frequently mutated in human lymphomas.

Roquin

A RING-type ubiquitin ligase that represses the expression of inducible T cell co-stimulator (ICOS), thereby restraining the development and function of T follicular helper cells. A mutation in the Roquin (also known as Rc3h1) gene results in lupus-like disease in mice.

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Tangye, S., Ma, C., Brink, R. et al. The good, the bad and the ugly — TFH cells in human health and disease. Nat Rev Immunol 13, 412–426 (2013). https://doi.org/10.1038/nri3447

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