T follicular helper cell programming by cytokine-mediated events

Abstract

CD4⁺ T cells, or T helper cells, are critical mediators and coordinators of adaptive immunity. Unique effector T helper cell populations have been identified that perform distinct functions in response to pathogenic infection. The T follicular helper (Tfh) cells are one such subset, which has been identified as the primary T-cell population responsible for interacting with B cells to promote effective antibody-mediated immune responses. Since their initial description at the turn of the century, and subsequent classification as a distinct T helper cell subset, there has been substantial interest in elucidating the regulatory mechanisms that govern Tfh cell formation. The collective insight from this body of work has demonstrated that Tfh cell differentiation is a complex and multistage process regulated by a litany of cell-intrinsic and cell-extrinsic factors. As with the development of the other recognized T helper cell subsets, specific cytokines exercise prominent roles in both the positive and negative regulation of Tfh cell development. However, the exact composition of, and stage-specific requirements for, these environmental factors in the governance of Tfh cell differentiation remain incompletely understood. In this review, we summarize what is known regarding the role of cytokines in both the promotion and inhibition of Tfh cell differentiation and function.

Keywords: T follicular helper cells; T helper cell differentiation; cytokines; transcription factors.

Figure 1

T follicular helper (Tfh) cell development and the impact of cytokine signals. Schematic depicting the multistage process of Tfh cell differentiation. The reported impacts of cytokine signals on murine Tfh cell development have been highlighted in red (negative) and green (positive). Tfh cell development is initiated upon antigen‐presenting‐cell‐mediated activation of naive CD4⁺ T cells in the presence of the indicated cytokines (1). This results in the up‐regulation of the Tfh lineage‐defining transcription factor B‐cell lymphoma 6 (Bcl‐6), as well as the expression of additional canonical Tfh genes including Cxcr5, programmed cell death protein 1 (PD‐1), and inducible T‐cell co‐stimulator (ICOS). Pre‐germinal centre (‘pre‐GC’) Tfh cells traffic to the T–B border, where they participate in cognate interactions with B cells (2). This results in the further up‐regulation of Tfh gene expression patterns including increased expression of Bcl‐6, Cxcr5, PD‐1 and ICOS (3). Subsequent cognate interactions between T and B lymphocytes result in the formation of the germinal centre and maintenance of the GC Tfh cell phenotype (4).

Figure 2

Cytokines that promote or inhibit murine follicular helper T (Tfh) cell differentiation. An illustrated diagram of the mechanisms by which cytokines regulate the development of Tfh cells in mice. Individual cytokines and the signal transducer and activator of transcription (STAT) transcription factors they activate are shown. Additionally, the impact of each cytokine on B‐cell lymphoma 6 (Bcl‐6) expression and Tfh cell development is indicated. It is important to note that the function of the depicted cytokines is not conserved across species, as transforming growth factor‐β (TGF‐β) signalling has been shown to negatively regulate Tfh development in mice, yet induces the expression of the Tfh gene programme in human cells.