Follicular helper T cells in immunity and systemic autoimmunity

Abstract

Follicular helper T (T(FH)) cells are essential for B-cell maturation and immunoglobulin production after immunization with thymus-dependent antigens. Nevertheless, the development and function of T(FH) cells have been less clearly defined than classic CD4(+) effector T-cell subsets, including T-helper-1 (T(H)1), T(H)2 and T(H)17 cells. As such, our understanding of the genesis of T(FH) cells in humans and their role in the development of autoimmunity remains incomplete. However, evidence from animal models of systemic lupus erythematosus (SLE) and patients with systemic autoimmune diseases suggests that these cells are necessary for pathogenic autoantibody production, in a manner analogous to their role in promotion of B-cell maturation during normal immune responses. In this Review, I discuss the findings that have increased our knowledge of T(FH)-cell development and function in normal and aberrant immune responses. Such information might improve our understanding of autoimmune diseases, such as SLE, and highlights the potential of T(FH) cells as therapeutic targets in these diseases.

Figure 1

The CD4⁺ T cell development paradigm. Differentiation of naive CD4⁺ T cells into different T-helper-cell subsets is dependent on factors present in the local environment, most prominently cytokines. The specific stimulatory conditions influence transcription factor expression, which determines the differentiation program that the T cell will follow and thus the cytokines that it will subsequently produce. The pattern of cytokine expression characterizes the individual T-helper-cell subsets and dictates their function in host defenses. Whereas the cytokine signals that promote the development of T_H1, T_H2, T_H17, and T_REG cells are well-defined, less is known about those that drive T_FH-cell formation, but seem to include IL-6 and IL-21. Abbreviations: BCL6, B-cell lymphoma 6; FOXP3, forkhead box protein 3; GATA3, GATA-binding factor 3; RORα, retinoid-related orphan receptor-α; RORγt, retinoid-related orphan receptor-γt; TBX21, T-box transcription factor TBX21; T_FH, follicular helper T; TGF-β, transforming growth factor-β; T_H1, T-helper-1; T_H2, T-helper-2; T_H17, T-helper-17; T_REG, regulatory T.

Figure 2

T_FH-cell development and T_FH-cell–B-cell collaboration in extrafollicular and GC responses. Naive T cells migrate to the T-cell zones of secondary lymphoid organs (here, the spleen) following a chemokine gradient of CCL19 and CCL21 that engages CCR7 on their surface (1). B cells localize to the B-cell follicle, directed by CXCL13 that engages CXCR5 on their plasma membrane (1). Upon antigen activation and co-stimulation by dendritic cells, nascent T_FH cells upregulate CXCR5, downregulate CCR7 and migrate to the T-cell–B-cell border (or interfollicular regions of lymph nodes), where they contact antigen-activated B cells that move towards the T-cell zone after upregulating CCR7 (2). The outcome of this interaction is development of extrafollicular foci (3), where short-lived plasmablasts produce antibodies, or GCs in the B-cell follicle (3). In both structures, T_FH cells promote B-cell maturation, inducing class switching and affinity selection, via cytokines —particularly IL-21 and IL-4—and cell-bound molecules—including CD40 ligand (4). T_FH-cell and GC B-cell development and function are dependent on the transcriptional regulator BCL6. The GC response leads to memory B cell and plasma cell formation (5). Abbreviations: BCL6, B-cell lymphoma 6; CCL19, CC-chemokine ligand 19; CCL21, CC-chemokine ligand 21; CCR7, CC-chemokine receptor 7; CXCL13, CXC-chemokine ligand 13; CXCR5, CXC-chemokine receptor 5; GC, germinal centre; T_FH, follicular helper T.

Figure 3

The interaction between T_FH cells and GC B cells. The former express molecules critical for survival and for maturation of the latter to memory B cells and plasma cells that produce class-switched immunoglobulin, including CD40L signaling via CD40 and the cytokines IL-4 and IL-21 signaling via their receptors. PD-1 on T_FH cells, via binding to its ligands on GC B cells, PD-L1 and especially PD-L2, promotes survival and selection of the latter cells. Abbreviations: BCR, B-cell receptor; CD40L, CD40 ligand; GC, germinal centre; ICOS, inducible T-cell co-stimulator; ICOS-L, inducible T-cell co-stimulator ligand; Ig, immunoglobulins; IL-4R, IL-4 receptor; IL-21R, IL-21 receptor; MHC, major histocompatibility complex; PD-1, programmed death-1; PD-L1, programmed death ligand 1; PD-L2, programmed death ligand 2; TCR, T-cell receptor; T_FH, follicular helper T.

Figure 4

Subsets of T cells that promote or regulate B-cell help. T_FH cells, critical for GC development and maturation, are reliant upon the transcription factor BCL6 for differentiation and function, as are extrafollicular T-helper cells that promote formation of the extrafollicular plasmablast response. Follicular helper iNKT cells, also reliant upon BCL6 for development, provide cognate help for B-cell maturation in extrafollicular foci and GCs—similar to T_FH and extrafollicular T-helper cells, respectively—resulting in the production of class-switched and affinity-matured antibodies to lipids. By contrast, T_FR cells regulate the T_FH and GC B-cell responses, providing a brake on development of autoimmune reactions. As for their B-cell helper counterparts, T_FR cells require BCL6 for development, but upregulate the BCL6 repressor, BLIMP-1, as well as expressing molecules associated with T_REG-cell development and function, including FOXP3, CTLA4, GITR and IL-10. Abbreviations: BCL6, B-cell lymphoma 6; BLIMP-1, B-lymphocyte-induced maturation protein 1; CD40L, CD40 ligand; CTLA4, cytotoxic T-lymphocyte-associated antigen 4; CXCR4, CXC-chemokine receptor 4; CXCR5, CXC-chemokine receptor 5; FOXP3, forkhead box protein 3; GC, germinal center; GITR, glucocorticoid-induced TNF-receptor-related protein; ICOS, inducible T-cell co-stimulator; iNKT, invariant natural killer T; PD-1, programmed death-1; TCR, T-cell receptor; T_FH, follicular helper T; T_FR, follicular regulatory T; T_REG, regulatory T.