Lead role for BCL-6 in T_FH cell development

The requirement for T cell help for B cells has been known for many years, but it is only recently that specialized T cells — T follicular helper (T_FH) cells — have been identified that express high levels of CXC-chemokine receptor 5 (CXCR5), which enables them to localize to B cell follicles during T cell-dependent immune responses. Although the phenotype of T_FH cells has been well characterized, the factors governing their differentiation are poorly understood. Now, three studies show that the transcription factor B cell lymphoma 6 (BCL-6) is a master regulator of T_FH cell differentiation.

As BCL-6 is selectively expressed by the T_FH cells in the T cell lineage, Yu et al. investigated the role of BCL-6 in T_FH cell lineage commitment. They generated mixed chimaeras by injecting BCL-6-deficient and BCL-6-sufficient fetal liver cells into recipient mice, which were then immunized with sheep red blood cells 8 weeks later. BCL-6-deficient T cells were unable to differentiate into T_FH cells, showing that BCL-6 is essential for the development of T_FH cells. Further experiments showed that T cell-restricted deficiency of BCL-6 also prevented the formation of germinal centres. BCL-6 expression was not required for the development of T_H1, T_H17 or regulatory T cells — in fact, overexpression of BCL-6 repressed the production of the key T_H1-type cytokine interferon-γ (IFNγ) and the T_H17-type cytokine interleukin-17 (IL-17). Nurieva et al. also reported that overexpression of BCL-6 in T cells induced T_FH cell differentiation and inhibited the differentiation of T_H1, T_H2 and T_H17 cells. BCL-6 expression was regulated by IL-6 and IL-21, and was required by both T and B cells for germinal centre interactions.

BCL-6 is a transcriptional repressor, so how does it specify T_FH cell fate? In the Yu et al. study, chromatin immunoprecipitation assays using human tonsil T_FH cells and B cells showed that BCL-6 bound to the promoters for the transcriptional regulators T-bet (also known as TBX21) and retinoic acid receptor-related orphan receptor-γt (RORγt), which determine T_H1 and T_H17 cell fate, respectively, resulting in the repression of IFNγ and IL-17 production. Furthermore, BCL-6 also suppressed the expression of microRNAs that are thought to repress T_FH cell gene expression.

Johnston et al. showed that BCL-6 was upregulated and B lymphocyte-induced maturation protein 1 (BLIMP1; also known as PRDM1), which antagonizes BCL-6, was strongly downregulated in T_FH cells compared with non-T_FH CD4⁺ T cells. Constitutive overexpression of BCL-6 resulted in almost all T cells becoming T_FH cells and enhanced both germinal centre formation and antibody responses. Expression of BCL-6 and differentiation of T_FH cells were shown to require cognate interaction with B cells. Further experiments showed that the absence of BCL-6 expression in CD4⁺ T cells prevented the formation of germinal centres. Retroviral overexpression of BLIMP1 prevented BCL-6 expression in CD4⁺ T cells and greatly reduced the differentiation of T_FH cells. Conversely, BLIMP1-deficient CD4⁺ T cells showed enhanced T_FH cell differentiation.

Taken together, these results show that BCL-6 is both necessary and sufficient for T_FH cell development and provide further evidence to support the idea that T_FH cells are a separate lineage of T_H cells.