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  • Review Article
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Follicular B helper T cells in antibody responses and autoimmunity

Nature Reviews Immunology volume 5, pages 853–865 (2005)Cite this article

Key Points

  • Germinal centres are crucial for long-lived antibody responses and are a fundamental feature of adaptive immune responses. The T cells that provide help to germinal-centre B cells were long considered to be T helper 2 (TH2) cells; however, non-polarized, CD4+ follicular B helper T (TFH) cells are now recognized to be the main providers of help to this B-cell subset.

  • TFH cells, as well as most B cells, express CXC-chemokine receptor 5 (CXCR5). This enables these cells to migrate towards the chemokine CXC-chemokine ligand 13 (CXCL13), which is expressed by follicular stromal cells, thereby facilitating T-cell–B-cell interactions.

  • In mice, differentiation into TFH cells has been shown to require signals from dendritic cells and CD4+CD3− accessory cells, including the ligation of CD28, CD30 and OX40. Antigen-specific B cells are also likely to influence TFH-cell commitment.

  • Molecules that are important for TFH-cell help to germinal-centre B cells include inducible T-cell co-stimulator (ICOS), CD40 ligand, interleukin-10 (IL-10) and signalling lymphocytic activation molecule (SLAM)-associated protein (SAP). The transcription factor B-cell lymphoma 6 (BCL-6) and the cytokine IL-21 are also likely to have important roles in TFH-cell differentiation and function.

  • The relationship of TFH cells to TH2 or TH1 cells is uncertain. TH1 and TH2 cytokines influence antibody responses and immunoglobulin class switching. It is possible that TH2 cells that receive appropriate signals enter the follicles, switch off IL-4 production and give rise to TFH cells.

  • Somatic hypermutation in germinal centres and the generation of new antibody specificities by B cells (which sometimes recognize self-antigens) requires that B cells receive selection signals from TFH cells that have themselves undergone stringent selection. Mutations in the roquin gene promote the differentiation or clonal expansion of self-reactive TFH cells, which leads to autoimmune disease. Therefore, control of T-cell help to germinal-centre B cells is a crucial checkpoint in peripheral T-cell tolerance.

  • Insufficient follicular T-cell help underlies certain immunodeficiencies, including X-linked lymphoproliferative syndrome (which is caused by a deficiency in SAP) and common variable immunodeficiency (which is caused by mutations in ICOS). In both of these conditions, there is impaired germinal-centre formation and an absence of memory B cells.

Abstract

T-cell help for B cells is essential for high-affinity antibody responses and B-cell memory. Recently, the identity of a discrete follicular population of T cells that has a crucial role in this process has become clearer. Similar to primed CD4+ T cells in the tonsils and memory CD4+ T cells in the peripheral blood, this follicular population of T cells expresses CXC-chemokine receptor 5 (CXCR5). Owing to their distinct homing preferences and helper function, these T cells differ from T helper 1 and T helper 2 cells and have been denoted follicular B helper T cells. Here, we outline the central role of this subset in normal and pathological immune responses.

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Figure 1: Follicular and extrafollicular pathways of B-cell differentiation.
Figure 2: Possible pathways of T-cell maturation into TFH cells.
Figure 3: Some of the basic molecular mechanisms of TFH-cell function.
Figure 4: Peripheral checkpoints that prevent autoantibody production by self-reactive B cells.

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Acknowledgements

This work was supported by the National Health and Medical Research Council (Australia), the Wellcome Trust (United Kingdom) and the Cooperative Research Centre for Asthma (Australia).

Author information

Authors and Affiliations

  1. Division of Immunology and Genetics, John Curtin School of Medical Research, The Australian National University, Canberra, 2601, Australia

    Carola G. Vinuesa

  2. Centenary Institute of Cancer Medicine and Cell Biology, Newtown, 2042, New South Wales, Australia

    Stuart G. Tangye

  3. Institute of Cell Biology, University of Bern, Baltzerstrasse 4, Bern, CH3012, Switzerland

    Bernhard Moser

  4. Arthritis and Asthma Research Program, The Garvan Institute of Medical Research, 384 Victoria Street, Sydney, 2010, New South Wales, Australia

    Charles R. Mackay

Authors
  1. Carola G. Vinuesa
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  2. Stuart G. Tangye
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  3. Bernhard Moser
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  4. Charles R. Mackay
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Correspondence to Charles R. Mackay.

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DATABASES

Entrez Gene

BCL-6

CD30

CD40

CD40L

CD57

CD84

CXCL13

CXCR5

ICOS

ICOSL

IL-10

IL-21

IL-21R

Ly9

OX40

OX40L

roquin

SAP

FURTHER INFORMATION

Carola Vinuesa's homepage

Charles Mackay's homepage

Glossary

RED PULP

The blood-filtering part of the spleen that is formed by sinuses. The sinuses are usually filled with blood and consist of reticular fibres, which are lined with specialized macrophages that form part of the reticuloendothelial system. The main function of the red pulp is to destroy senescent erythrocytes. Long-lived plasma cells also localize to this region of the spleen.

GERMINAL CENTRE

A lymphoid structure that arises within follicles after immunization with, or exposure to, a T-cell-dependent antigen. It is specialized for facilitating the development of high-affinity, long-lived plasma cells and memory B cells.

SOMATIC HYPERMUTATION

Point mutations that occur in cycling centroblasts and are targeted to the immunoglobulin variable-region gene segments. Some mutations might generate a binding site with increased affinity for the specific antigen, but others can lead to loss of antigen recognition by the B-cell receptor and generation of a self-reactive B-cell receptor.

CLASS-SWITCH RECOMBINATION

The process by which proliferating B cells rearrange their DNA to switch from expressing IgM (or another class of immunoglobulin) to expressing a different immunoglobulin heavy-chain constant region, thereby producing antibody with different effector functions.

CENTROBLAST

A proliferating germinal-centre B cell, which undergoes somatic hypermutation and immunoglobulin class switching.

CENTROCYTE

The non-dividing progeny of a centroblast. These cells need to be selected on the basis of affinity for antigen, following interaction with immune complexes that are associated with follicular dendritic cells, and ability to elicit help from follicular B helper T (TFH) cells.

MANTLE ZONE

The area of a secondary follicle that surrounds the germinal centre and contains IgD+ naive, resting B cells.

LIGHT ZONE

The area of the germinal centre that is most distant from the T-cell zone. These areas contain a rich network of follicular dendritic cells, which hold antigen on their surface. They are filled with centrocytes and small numbers of follicular T cells.

CHEMOATTRACTANT-RECEPTOR HOMOLOGOUS MOLECULE EXPRESSED BY TH2 CELLS

(CRTH2). A cell-surface marker for human T helper 2 (TH2) cells.

REGULATORY T CELLS

(TReg cells). A small population of CD4+ T cells that expresses the transcription factor forkhead box P3 (FOXP3) and has regulatory (that is, suppressor) activity towards other T cells that are stimulated through their T-cell receptor. An absence of TReg cells or their dysfunction is associated with severe autoimmunity.

CENTRAL MEMORY T CELLS

Memory T cells that express L-selectin and CC-chemokine receptor 7 (CCR7) and have the capacity to circulate from the blood to the secondary lymphoid organs. They have a non-polarized differentiation state in that they secrete interleukin-2 but not interferon-γ or interleukin-4; however, on restimulation, they rapidly differentiate into cytokine-producing effector cells.

SRC HOMOLOGY 2 DOMAIN

(SH2 domain). A protein domain of ∼100 amino-acid residues that is found in many intracellular signal-transducing proteins. It interacts with high affinity with phosphotyrosine-containing target peptide sequences in a sequence-specific, and usually phosphorylation-dependent, manner.

SYSTEMIC LUPUS ERYTHEMATOSUS

(SLE). An autoimmune disorder in which antibodies are raised against one's own DNA and form immune complexes that cause end-organ damage. It classically presents with a butterfly-shaped rash across the cheek bones, which causes a wolf-like appearance (lupus being Latin for wolf).

COMPLETE FREUND'S ADJUVANT

(CFA). An oil that contains an emulsifying agent and killed mycobacteria, which increase the immune response to an immunogen. For administration, a water-in-oil emulsion is made with a solution that contains the immunogen of interest.

NON-OBESE DIABETIC MICE

(NOD mice). A mouse strain that has a polygenic susceptibility to spontaneous development of autoimmune, type 1 diabetes. The main component of susceptibility is the unique MHC haplotype H2g7.

MOLECULAR MIMICRY

A mechanism by which a peptide from a foreign antigen that is presented to a T cell closely resembles part of a self-protein, thereby triggering an autoimmune reaction.

SANROQUE MICE

An autoimmune strain of mice that carries a loss-of-function mutation in the gene roquin. These mice have a T-cell-mediated systemic-lupus-erythematosus-like syndrome and severe autoimmune diabetes when on a susceptible genetic background.

EFFECTOR MEMORY T CELLS

Cells that have an L-selectin− CCR7 phenotype. They have immediate effector functions, including rapid production of cytokines (such as interferon-γ or interleukin-4), and they migrate to sites of inflammation, such as the skin and the gut.

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Vinuesa, C., Tangye, S., Moser, B. et al. Follicular B helper T cells in antibody responses and autoimmunity. Nat Rev Immunol 5, 853–865 (2005). https://doi.org/10.1038/nri1714

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