Follicular helper T cells: new insights into mechanisms of autoimmune diseases

Abstract

Background: Autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, etc) are characterized by the production of autoantibodies against one's own cell components, resulting in the dysfunction of normal organs. At present, therapies for autoimmune diseases involve a variety of nonspecific antiinflammatory and immunosuppressive agents with significant side effects. Current studies have suggested that the germinal center (GC) may be the pathogenic hot spot for the production of autoantibodies in autoimmune disease. Events occurring in the GC-such as the selection of high-affinity B cells, proliferation of B cells, and differentiation of B cells into plasma cells-all depend on T cells. Follicular helper T (Tfh) cells are a recently identified T-cell subset, named for their location in GCs. Tfh cells are characterized by their signature transcription factor (B-cell lymphoma 6), surface molecules (CD40 ligand, chemokine [C-X-C] receptor 5, inducible T-cell costimulator, programmed cell death protein-1, etc), and cytokines (interleukin [IL]-21, IL-6, IL-10, etc). Through these signals, Tfh cells help B cells form GCs and drive B cells to differentiate into memory B cells and plasma cells that produce antibodies. However, uncontrolled generation of Tfh cells in the GCs or peripherals could lead to autoimmunity. Recent studies from our group and others have shown that Tfh cells are expanded in the peripheral blood of patients and in the lymphoid tissues of mice with lupus or rheumatoid arthritis and play an important role in promoting pathogenic autoantibody production.

Methods: In this review, we summarize the latest immunologic findings regarding the characteristics and development of Tfh cells, their relation to other CD4(+) T-cell subsets, and the function of Tfh cells in normal immune response and autoimmune diseases.

Conclusion: A clear understanding of the mechanisms of Tfh cell-mediated immunity and pathology may lead to the development of novel therapeutic targets in autoimmune diseases.

Keywords: Antibody formation; autoimmune diseases; germinal center.

Figure 1.

Schematic model of follicular helper T cell (Tfh) development and collaboration with B cells in secondary lymphoid organs. Naïve T cells in the peripheral blood migrate to the T-cell zone in the secondary lymphoid organs (tonsil, spleen, etc) following the gradient of (C-C motif) chemokine ligand (CCL) 19 and CCL21, by engaging to their counterpart (chemokine receptor type 7 [CCR7] and P-selectin glycoprotein ligand-1 [PSGL-1]). T cells become activated (Ta) by recognizing the antigen (Ag) provided by dendritic cells. Dendritic cells provide costimulatory signals to promote T-cell differentiation, resulting in the generation of T-cell subsets. With downregulation of CCR7 and PSGL-1 and upregulation of the expression of chemokine (C-X-C) receptor type 5 (CXCR5) and B-cell lymphoma 6 (BCL-6), Tfh cells are generated and migrate to the T-B border to interact with the antigen-activated B cells. The outcome for this interaction is the development of extrafollicular foci where B cells differentiate into short-lived plasmablasts and/or form germinal centers (GCs). In the GCs, Tfh cells promote B-cell maturation with clone expansion, somatic hypermutation, and class switching through pairs of surface molecules and cytokines (such as interleukin [IL]-21, etc). The interaction of Tfh and B cells leads to the generation of memory B cells and long-lived antibody-producing plasma cells. BCR, B cell receptor; CD40L, CD40 ligand; CXCL13, C-X-C motif chemokine 13; GATA3, GATA binding protein 3; ICOS, inducible T cell costimulator; ICOSL, ICOS ligand; IL-21R, IL-21 receptor; MHC, major histocompatibility complex; PD-1, programmed cell death protein-1; PD-1L, PD-1 ligand; SAP, signaling lymphocytic activation molecule-associated protein; TCR, T cell receptor; Th1, type 1 helper T cells; Th2, type 2 helper T cells.

Figure 2.

T helper cell lineage development and function. The cytokines produced by dendritic cells regulate the T helper cell lineage (Th1, Th2, Th17, T regulatory [Treg], and follicular helper T cells [Tfh]). Each of them exhibits a unique phenotype, cytokine, and transcriptional profile and exerts different functions in immune response. BCL-6, B cell lymphoma 6 protein; CCR, C-C chemokine recetor; CXCR, CXC chemokine receptor; Foxp3, forkhead box P3; IFN, interferon; IL, interleukin; RORs, retinoid-acid receptor related orphan receptors; STAT, signal transducer and activator of transcription; TGF-β, transforming growth factor-beta; TNF, tumor necrosis factor.