Transcription tipping points for T follicular helper cell and T-helper 1 cell fate commitment

Abstract

During viral infection, immune cells coordinate the induction of inflammatory responses that clear infection and humoral responses that promote protection. CD4+ T-cell differentiation sits at the center of this axis. Differentiation toward T-helper 1 (Th1) cells mediates inflammation and pathogen clearance, while T follicular helper (Tfh) cells facilitate germinal center (GC) reactions for the generation of high-affinity antibodies and immune memory. While Th1 and Tfh differentiation occurs in parallel, these CD4+ T-cell identities are mutually exclusive, and progression toward these ends is determined via the upregulation of T-bet and Bcl6, respectively. These lineage-defining transcription factors act in concert with multiple networks of transcriptional regulators that tip the T-bet and Bcl6 axis in CD4+ T-cell progenitors to either a Th1 or Tfh fate. It is now clear that these transcriptional networks are guided by cytokine cues that are not only varied between distinct viral infections but also dynamically altered throughout the duration of infection. Thus, multiple intrinsic and extrinsic factors combine to specify the fate, plasticity, and function of Th1 and Tfh cells during infection. Here, we review the current information on the mode of action of the lineage-defining transcription factors Bcl6 and T-bet and how they act individually and in complex to govern CD4+ T-cell ontogeny. Furthermore, we outline the multifaceted transcriptional regulatory networks that act upstream and downstream of Bcl6 and T-bet to tip the differentiation equilibrium toward either a Tfh or Th1 fate and how these are impacted by dynamic inflammatory cues.

Conversations that count: Cellular interactions that drive T cell fate

“…Still, there exists critical cytokine and transcriptional tipping points that can lead to a preference for differentiation toward either T FH and CD4+ T cell effectors. 9 Functional heterogeneity within T FH populations is a newly established concept. During B cell interactions within the germinal center, T FH cells can secrete multiple cytokines, IL-21, IL-4, IL-2, IL-9, IL-10, IL-13, and IFNγ.…”

“…Bcl6 acts primarily to downregulate Blimp1 and to prevent effector T H fates. 9,69,72 Bcl6 also represses Gata3, the T H2 master regulator, RORγt, required for F I G U R E 1 Circular relationship between transcriptional and environmental regulators of T cell differentiation. Following initial contact with dendritic cells, T cells begin to upregulate the transcription factors that regulate diverging fates.…”

“…80 Interestingly, in CD8+ T cells, this expression is dependent on IL-21, while in T FH differentiation, the requirement for IL-21 remains controversial. 9 In memory precursors, Bcl6 binds directly to the Tcf7 locus, driving TCF-1 expression, which is critical for memory differentiation. 27 Further, the forced expression of TCF-1 in Bcl6-deficient mice restores generation of memory precursors, demonstrating that Bcl6 functions upstream of TCF-1 as a critical regulator of memory formation during acute viral infection.…”

“…In addition to direct repression, this is achieved by forming complexes with other lineage-defining transcription factors, such as RORgt, GATA3, and Bcl6, to block T H17 , T H2 , and T FH differentiation, respectively. 9,94,95 Formation of these complexes sequesters these other lineage-defining factors away from their DNA binding sequences and thus blocks their action. 91,96 Additionally, T-bet cooperates with RUNX3 to antagonize GATA3 activity and also silences the Il4 locus to repress IL-4 expression.…”

“…interactions occur, and the dendritic cell subsets involved, plays a critical role in establishing the gene networks that determine effector and memory differentiation for both CD4+ and CD8+ T cells. 1,[7][8][9][10][11][12][13][14][15] Following activation, CD4+ T cells can differentiate into a diverse set of effector helper cells. Each helper lineage is specified by distinct transcriptional regulators and cytokines that orchestrate a coordinated attack for the eradication of a specific type of pathogen.…”