Follicular Helper T Cells

Abstract

Follicular helper T (Tfh) cells are a subset of helper T cells with specialised functions to support high‐affinity and long‐term antibody responses. Tfh cells express high levels of transcription factor Bcl6, chemokine receptor CXCR5, cytokine IL‐21 and costimulatory receptor PD‐1 and ICOS, showing a phenotype distinct from other helper T‐cell subsets. The differentiation and function of Tfh cells are regulated by a unique molecular program orchestrated by the transcriptional factor Bcl6. The knowledge of Tfh cells provides new insights into the physiopathology of many human diseases, including immunodeficiency, autoimmune disease, infection and cancer.

Key Concepts

  • Tfh cells are a helper T‐cell subset.
  • Tfh cells regulate antibody response.
  • CXCR5 is an important functional marker for Tfh cells.
  • The ICOS–Bcl6 pathway critically regulates the differentiation of Tfh cells.
  • Certain primary immunodeficiencies show defects in Tfh cells.
  • Aberrant and/or excessive Tfh function promotes autoimmune diseases.

Keywords: Tfh cells; antibody; CXCR5; Bcl6; ICOS; disease

Figure 1. Tfh help in GC formation and antibody response. Upon activation, naïve CD4+ T cells differentiate into precursor Tfh (pre‐Tfh) cells with upregulated CXCR5 and downregulated CCR7. These pre‐Tfh cells migrate towards the T–B border and/or the interfollicular zone, where they encounter antigen‐primed B cells. The cognate T–B interaction promotes their proliferation and further differentiation. Some of these B cells will differentiate into early memory B cells and extrafollicular plasmablasts that generate short‐lived plasma cells. Alternatively, these B cells can migrate into the centre of follicles to initiate GCs with the help from GC Tfh cells. GC B cells in the dark zone (DZ) undergo somatic hypermutation, while in the light zone (LZ) they compete for antigens deposited on the follicular dendritic cells (FDCs) and the help from GC Tfh cells. High‐affinity clones will be selected to differentiate into long‐lived plasma cells and memory B cells to exit GC. Thymic‐derived Foxp3+ Treg (tTreg) cells could upregulate CXCR5 and enter B‐cell follicles. These follicular regulatory T (Tfr) cells inhibit antibody response.
Figure 2. Tfh differentiation and memory formation. Activated CD4+ T cells can differentiate into distinct Th subsets. The differentiation is induced by the cytokine milieu and controlled by master transcription factors for each Th subset. Bcl6 specifically promotes Tfh‐cell differentiation. Precursor Tfh (pre‐Tfh) cells are generated in T–B border and/or interfollicular zone. They express PD‐1 and CXCR5 but a low amount of Bcl6 and CCR7. Pre‐Tfh cells can enter into circulation. Mature GC Tfh cells express a high level of Bcl6, CXCR5 and PD‐1 with little expression of CCR7. Following the resolution of GCs, some Tfh cells remain the expression of CXCR5 and persist in the outer follicle.
Figure 3. Molecular pathways that regulate Tfh‐cell differentiation. As the master transcription factor, Bcl6 is necessary and sufficient to direct Tfh‐cell differentiation. It directly represses transcription factors for the alternative differentiation of activated helper T cells to effector Th1, Th2 and Th17 cells. Bcl6 also antagonises with Blimp1, which inhibits CXCR5 expression. c‐Maf directly promotes the expression of IL‐21. Both BATF and IRF4 are required for Tfh‐cell differentiation. ICOS signalling specifically promotes Tfh‐cell differentiation. Through the PI3K signalling, ICOS activation induces the degradation of Foxo1, a negative regulator of Bcl6. SAP binds to the cytoplasmic tail of SLAM and related receptors and stabilises the cognate T–B interaction. miR‐17∼92 enhances PI3K signalling that is essential for Tfh‐cell differentiation. As a signature cytokine secreted by Tfh cells, IL‐21 sustains the differentiation and maintenance of Tfh cells. In contrast, IL‐2 preferentially activates Stat5, which inhibits the Tfh differentiation.
Figure 4. Tfh cells in health and disease. (a) Mutations in key Tfh molecules are implicated in a number of primary immunodeficiency diseases. SAP deficiency leads to abrogation of signal transduction through SLAM family of receptors, resulting in abortive Tfh–B cells conjugation. Patients developed X‐linked lymphoproliferative (XLP) syndrome. ICOS deficiency impairs the Tfh differentiation, leading to reduced GC response and memory formation. Patients developed common variable immunodeficiency (CVID). CD40L deficiency severely blocks T‐cell priming and GC formation. Patients developed X‐linked immunodeficiency with hyperimmunoglobulin M (XHIGM). (b) Excess and/or hyperactive Tfh cells can induce increased proliferation of B cells and indiscriminately provide help to autoreactive B cells, contributing to autoimmunity in diseases such as systemic lupus erythematosus (SLE), Sjogren syndrome (SS), autoimmune thyroid disease (AITD) and juvenile dermatomyositis (JD). (c) Increased frequency of infected Tfh cells forms a latent viral reservoir in HIV infection, but the Tfh helper function seems impaired in HIV and other infections. (d) Angioimmunoblastic T‐cell lymphoma (AITL) demonstrates a Tfh phenotype. On the other hand, infiltration by Tfh cells in certain kinds of solid tumours is associated with an improved prognosis, probably due to Tfh function to support antitumour immune response of NK cells and CD8 T cells.
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Chen, Yaping, Atnerkar, Anurag, and Yu, Di(Jan 2016) Follicular Helper T Cells. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024155]