Early Th1 Cell Differentiation Is Marked by a Tfh Cell-like Transition

Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Immunity (Impact Factor: 21.56). 12/2011; 35(6):919-31. DOI: 10.1016/j.immuni.2011.11.012
Source: PubMed


Follicular helper T (Tfh) cells comprise an important subset of helper T cells; however, their relationship with other helper lineages is incompletely understood. Herein, we showed interleukin-12 acting via the transcription factor STAT4 induced both Il21 and Bcl6 genes, generating cells with features of both Tfh and Th1 cells. However, STAT4 also induced the transcription factor T-bet. With ChIP-seq, we defined the genome-wide targets of T-bet and found that it repressed Bcl6 and other markers of Tfh cells, thereby attenuating the nascent Tfh cell-like phenotype in the late phase of Th1 cell specification. Tfh-like cells were rapidly generated after Toxoplasma gondii infection in mice, but T-bet constrained Tfh cell expansion and consequent germinal center formation and antibody production. Our data argue that Tfh and Th1 cells share a transitional stage through the signal mediated by STAT4, which promotes both phenotypes. However, T-bet represses Tfh cell functionalities, promoting full Th1 cell differentiation.

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    • "With regards to the relationship between TFH cells and other CD4+ T-cell subsets, a negative regulation exists as Bcl6 represses the expression or function of the master regulators of other Th-cell lineages, i.e., T-bet (Th1), GATA3 (Th2), and RORγt (Th17) (75–77). However, this effect appears to be partial, as TFH cells can produce IFN-γ (82), IL-4 (83, 84), or IL-17 (85), hallmarks of Th1, Th2, and Th17 cells. "
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    • "Tfh cells are found mainly in lymphoid tissue but are rare in the circulation. Although Th1 cells can re-differentiate to Tfh-like cells [63], Tbet-deficient CD4 T cells have an increased ability to generate Tfh cells, both in vivo and in vitro [64]. Thus Tbet may suppress the differentiation of Tfh cells, and the Thpp cells (lacking Tbet- expression) might have an increased ability to differentiate into the Tfh cells that drive the antibody response that is important for protection against influenza. "
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    PLoS ONE 05/2014; 9(5):e95986. DOI:10.1371/journal.pone.0095986 · 3.23 Impact Factor
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    • "Upon transduction, there was substantial silencing of STAT1 (79%, Figures S5A and S5B), and a large reduction in clonal expansion of transduced cells (Figure S5C). We found a slight but reproducible reduction in T-bet expression after transfer into WT congenic hosts (Figure S5D), which was not surprising given that STAT4 has also been shown to drive T-bet expression (Nakayamada et al., 2011). Despite differences in clonal expansion, there were no differences in Tfh cells or Bcl6 expression at 8 dpi (Figures S5E and S5F). "
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