Immune Netw.  2014 Feb;14(1):21-29. 10.4110/in.2014.14.1.21.

Insights into the Role of Follicular Helper T Cells in Autoimmunity

• Park HJ
• Kim DH
• Lim SH
• Kim WJ
• Youn J
• Choi YS
• Choi JM

• KMID: 1508825
• DOI: http://doi.org/10.4110/in.2014.14.1.21

Abstract

Follicular helper T (TFH) cells are recently highlighted as their crucial role for humoral immunity to infection as well as their abnormal control to induce autoimmune disease. During an infection, naive T cells are differentiating into TFH cells which mediate memory B cells and long-lived plasma cells in germinal center (GC). TFH cells are characterized by their expression of master regulator, Bcl-6, and chemokine receptor, CXCR5, which are essential for the migration of T cells into the B cell follicle. Within the follicle, crosstalk occurs between B cells and TFH cells, leading to class switch recombination and affinity maturation. Various signaling molecules, including cytokines, surface molecules, and transcription factors are involved in TFH cell differentiation. IL-6 and IL-21 cytokine-mediated STAT signaling pathways, including STAT1 and STAT3, are crucial for inducing Bcl-6 expression and TFH cell differentiation. TFH cells express important surface molecules such as ICOS, PD-1, IL-21, BTLA, SAP and CD40L for mediating the interaction between T and B cells. Recently, two types of microRNA (miRNA) were found to be involved in the regulation of TFH cells. The miR-17-92 cluster induces Bcl-6 and TFH cell differentiation, whereas miR-10a negatively regulates Bcl-6 expression in T cells. In addition, follicular regulatory T (TFR) cells are studied as thymus-derived CXCR5+PD-1+Foxp3+ Treg cells that play a significant role in limiting the GC response. Regulation of TFH cell differentiation and the GC reaction via miRNA and TFR cells could be important regulatory mechanisms for maintaining immune tolerance and preventing autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Here, we review recent studies on the various factors that affect TFH cell differentiation, and the role of TFH cells in autoimmune diseases.

Keyword

Follicular helper T cells; Germinal Center; Follicular regulatory T cells; Cytokines; Autoimmunity

MeSH Terms

Arthritis, Rheumatoid
Autoimmune Diseases
Autoimmunity*
B-Lymphocytes
CD40 Ligand
Cell Differentiation
Cytokines
Germinal Center
Immune Tolerance
Immunity, Humoral
Interleukin-6
Lupus Erythematosus, Systemic
Memory
MicroRNAs
Negotiating
Plasma Cells
Recombination, Genetic
T-Lymphocytes
T-Lymphocytes, Helper-Inducer*
T-Lymphocytes, Regulatory
Transcription Factors
CD40 Ligand
Cytokines
Interleukin-6
MicroRNAs
Transcription Factors

Figure

• 

  Figure 1 Molecular mechanisms of Bcl-6 expression in T cells. Bcl-6, the master regulator of TFH cell differentiation is controlled by a complex signaling pathway. Co-stimulatory molecules such as CD28 and ICOS activate PI3K to induce Bcl-6 expression. PTEN, PHLPP2 inhibit Bcl-6 expression through interfering PI3K signaling and Foxo1 directly inhibits Bcl-6 expression. Various cytokines, such as IL-6, IL-21, IL-12, and IFN-γ induce Bcl-6 expression through JAK-STAT signaling pathway while high level of IL-2 in combination with IL-12 induces T-bet to inhibit Bcl-6. Blimp-1 and Bcl-6 is reciprocally regulating each other to make a decision of effector T cell fate between TFH and non-TFH effector cells. Some miRNA such as miR-17-92 induces Bcl-6 expression by interfering phosphatases, which inhibit PI3K signaling pathway while miR-10a directly inhibits Bcl-6 expression.

• 

  Figure 2 Germinal center reaction controlled by TFH and TFR cells. Naïve T cells following stimulation with TcR and co-stimulatory molecules with IL-6 and IL-21 by dendritic cells can differentiate into TFH cells and migrate to the CXCL13-rich B cell follicle region. In the B cell follicle, TFH cells interact with B cells via TcR and co-stimulatory molecules such as ICOS and CD40L. Upon interaction between TFH cells and B cells, IL-4 and IL-21 from TFH cells allow B cells to differentiate into memory B cells or plasma cells, which are involved in long-lasting antibody production. TFR cells derived from nTreg precursor cells from the thymus by expressing Bcl-6 and CXCR5 migrate to B cell follicle and inhibit both TFH cell and B cell function.

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