Key Points
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T follicular helper (TFH) cells are a specialized subset of CD4+ T helper (TH) cells that are found in the B cell follicle during germinal centre reactions. TFH cells provide help to B cells through the provision of soluble factors and cell surface molecules that promote the production of high-affinity class-switched antibodies.
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TFH cells express several molecules in common with all recently activated CD4+ T cells but are distinguished from other fully differentiated TH cell subsets by their germinal centre location and by continued high expression of CXC-chemokine receptor 5 and interleukin-21.
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Support for the lineage specification of TFH cells comes from recent studies showing that the transcriptional repressor B cell lymphoma 6 (BCL-6) is required for TFH cell differentiation. Studies suggest that BCL-6 suppresses the differentiation of TH1 and TH17 cells and supports the differentiation of TFH cells.
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The differentiation pathway of TFH cells remains controversial. Recent studies have focused on the relationship between TFH cells and other TH cell subsets. Interaction with, and adhesion to, B cells is crucial for 'selecting' TFH cells from a pool of high-affinity T cell clones, and recent studies support the notion that TFH cells and other TH cell subsets share common cytokine-competent precursors and retain a degree of plasticity during their differentiation.
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TFH cells express cell surface markers that are associated with exhausted T cells. However, the identification of TFH cells that remain in B cell follicles after the resolution of the germinal centre reaction offers insight into the fate of TFH cells.
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TFH cells that deliver inappropriate helper signals to B cells are likely to underpin antibody-mediated autoimmune diseases, and studies indicate that certain T cell lymphomas share many similarities with those of TFH cells.
Abstract
The seminal studies characterizing T follicular helper (TFH) cells described a non-polarized CD4+ T cell population with a unique ability to home to B cell follicles and to induce antibody production by B cells. In the past few years, the study of TFH cells has enjoyed a renaissance and there has been a surge of research activity aimed at understanding the function and differentiation of these important cells. This Review focuses on the current progress in TFH cell biology and the important questions that remain unanswered. Particular attention is paid to recent studies that support the idea that TFH cells are a separate T cell lineage and those that probe the relationship of TFH cells to other T helper cell subsets.
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Acknowledgements
I would like to thank H. McGuire, A. Basten and S. Tangye for their helpful comments on the manuscript.
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Glossary
- Somatic hypermutation
-
A unique mutation mechanism that is targeted to the variable regions of rearranged immunoglobulin gene segments. Combined with the selection for B cells that produce high-affinity antibody, somatic hypermutation leads to affinity maturation of B cells in germinal centres.
- 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.
- Asymmetrical cell division
-
A type of division that produces two daughter cells with different properties. This is in contrast to normal cell divisions, which give rise to equivalent daughter cells. Notably, stem cells can divide asymmetrically to give rise to two distinct daughter cells: one copy of themselves and one cell programmed to differentiate into another cell type.
- TH17 cell
-
A subset of CD4+ T helper cells that produce IL-17 and that are thought to be important in inflammatory and autoimmune diseases. Their generation involves IL-21 and IL-23, as well as the transcription factors RORγt and STAT3.
- Sanroque mice
-
An autoimmune strain of mouse that has a loss-of-function mutation in the gene roquin (also known as Rc3h1). These mice develop a T cell-mediated systemic lupus erythematosus-like syndrome and severe autoimmune diabetes when bred onto a susceptible genetic background.
- X-linked lymphoproliferative disease
-
Individuals with X-linked lymphoproliferative disease have complicated immune dysfunctions, often triggered by infection with Epstein–Barr virus. Many patients develop fatal B cell lymphoproliferation. The gene that encodes SAP is mutated in these patients.
- Follicular DCs
-
Specialized non-haematopoietic stromal cells that reside in the follicles and germinal centres. These cells have long dendrites, but are not related to dendritic cells, and carry intact antigen on their surface.
- IL-4-reporter mice
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Genetically engineered knock-in mice in which the gene encoding IL-4 has been replaced by sequences that encode a reporter molecule, such as green fluorescent protein (GFP). When the IL-4 promoter region is activated, GFP is expressed and GFP+ cells can be seen by flow cytometry.
- Activation-induced cytidine deaminase
-
An enzyme that is required for two crucial events in the germinal centre: somatic hypermutation and class switch recombination.
- Experimental autoimmune encephalomyelitis
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An experimental model for the human disease multiple sclerosis. Autoimmune disease is induced in experimental animals by immunization with myelin or peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.
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King, C. New insights into the differentiation and function of T follicular helper cells. Nat Rev Immunol 9, 757–766 (2009). https://doi.org/10.1038/nri2644
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DOI: https://doi.org/10.1038/nri2644
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