Follicular helper T cells (TFH cells) are specialized effector CD4+ T cells that help B cells develop germinal centers and memory. Crotty and colleagues show that the transcription factors LEF-1 and TCF-1 are required for early TFH differentiation. Follicular helper T cells (TFH cells) are specialized effector CD4+ T cells that help B cells develop germinal centers (GCs) and memory. However, the transcription factors that regulate the differentiation of TFH cells remain incompletely understood. Here we report that selective loss of Lef1 or Tcf7 (which encode the transcription factor LEF-1 or TCF-1, respectively) resulted in TFH cell defects, while deletion of both Lef1 and Tcf7 severely impaired the differentiation of TFH cells and the formation of GCs. Forced expression of LEF-1 enhanced TFH differentiation. LEF-1 and TCF-1 coordinated such differentiation by two general mechanisms. First, they established the responsiveness of naive CD4+ T cells to TFH cell signals. Second, they promoted early TFH differentiation via the multipronged approach of sustaining expression of the cytokine receptors IL-6Rα and gp130, enhancing expression of the costimulatory receptor ICOS and promoting expression of the transcriptional repressor Bcl6.

The cellular and molecular events that drive early innate lymphoid cell (ILC) development remain poorly understood. Bhandoola and colleagues used a reporter mouse to identify a new subset of early ILC progenitors (EILPs) that express high amounts of TCF-1. The cellular and molecular events that drive the early development of innate lymphoid cells (ILCs) remain poorly understood. We show that the transcription factor TCF-1 is required for the efficient generation of all known adult ILC subsets and their precursors. Using novel reporter mice, we identified a new subset of early ILC progenitors (EILPs) expressing high amounts of TCF-1. EILPs lacked efficient T and B lymphocyte potential but efficiently gave rise to NK cells and all known adult helper ILC lineages, indicating that they are the earliest ILC-committed progenitors identified so far. Our results suggest that upregulation of TCF-1 expression denotes the earliest stage of ILC fate specification. The discovery of EILPs provides a basis for deciphering additional signals that specify ILC fate.

Xue and colleagues show that the transcription factors Tcf1 and Lef1 suppress CD4+ T lineage genes in CD8+ T cells through intrinsic histone deacetylase (HDAC) activity. The CD4+ and CD8+ T cell dichotomy is essential for effective cellular immunity. How individual T cell identity is established remains poorly understood. Here we show that the high-mobility group (HMG) transcription factors Tcf1 and Lef1 are essential for repressing CD4+ lineage–associated genes including Cd4, Foxp3 and Rorc in CD8+ T cells. Tcf1- and Lef1-deficient CD8+ T cells exhibit histone hyperacetylation, which can be ascribed to intrinsic histone deacetylase (HDAC) activity in Tcf1 and Lef1. Mutation of five conserved amino acids in the Tcf1 HDAC domain diminishes HDAC activity and the ability to suppress CD4+ lineage genes in CD8+ T cells. These findings reveal that sequence-specific transcription factors can utilize intrinsic HDAC activity to guard cell identity by repressing lineage-inappropriate genes.

The role of CD4⁺ cytotoxic T cells (CTLs) in hepatocellular carcinoma (HCC) remains obscure. This study characterized CD4⁺ CTLs in HCC patients and further elucidated the associations between CD4⁺ CTLs and HCC disease progression. In all, 547 HCC patients, 44 chronic hepatitis B (CHB) patients, 86 liver cirrhosis (LC) patients, and 88 healthy individuals were enrolled in the study. CD4⁺ CTLs were defined by flow cytometry, immunohistochemistry, and lytic granule exocytosis assays. A multivariate analysis of prognostic factors for overall survival was performed using the Cox proportional hazards model. Circulating and liver-infiltrating CD4⁺ CTLs were found to be significantly increased in HCC patients during early stage disease, but decreased in progressive stages of HCC. This loss of CD4⁺ CTLs was significantly correlated with high mortality rates and reduced survival time of HCC patients. In addition, the proliferation, degranulation, and production of granzyme A, granzyme B, and perforin of CD4⁺ CTLs were inhibited by the increased forkhead/winged helix transcription factor (FoxP3⁺) regulatory T cells in these HCC patients. Further analysis showed that both circulating and tumor-infiltrating CD4⁺ CTLs were independent predictors of disease-free survival and overall survival after the resection of the HCC. Conclusion: The progressive deficit in CD4⁺ CTLs induced by increased FoxP3⁺ regulatory T cells was correlated with poor survival and high recurrence rates in HCC patients. These data suggest that CD4⁺ CTLs may represent both a potential prognostic marker and a therapeutic target for the treatment of HCC. (HEPATOLOGY 2013)

Xue and colleagues show that Runx3−/− CD8+ T effector cells aberrantly upregulate genes characteristic of TFH cell lineage and exhibit impaired induction of cytotoxic molecules. Activated CD8+ T cells differentiate into cytotoxic effector (TEFF) cells that eliminate target cells. How TEFF cell identity is established and maintained is not fully understood. We found that Runx3 deficiency limited clonal expansion and impaired upregulation of cytotoxic molecules in TEFF cells. Runx3-deficient CD8+ TEFF cells aberrantly upregulated genes characteristic of follicular helper T (TFH) cell lineage, including Bcl6, Tcf7 and Cxcr5. Mechanistically, the Runx3-CBFβ transcription factor complex deployed H3K27me3 to Bcl6 and Tcf7 genes to suppress the TFH program. Ablating Tcf7 in Runx3-deficient CD8+ TEFF cells prevented the upregulation of TFH genes and ameliorated their defective induction of cytotoxic genes. As such, Runx3-mediated Tcf7 repression coordinately enforced acquisition of cytotoxic functions and protected the cytotoxic lineage integrity by preventing TFH-lineage deviation.