A Synchronous IRF4-Dependent Gene Regulatory Network in B and Helper T Cells Orchestrating the Antibody Response

Abstract

Control of diverse pathogens requires an adaptive antibody response, dependent on cellular division of labor to allocate antigen-dependent B- and CD4⁺ T-cell fates that collaborate to control the quantity and quality of antibody. This is orchestrated by the dynamic action of key transcriptional regulators mediating gene expression programs in response to pathogen-specific environmental inputs. We describe a conserved, likely ancient, gene regulatory network that intriguingly operates contemporaneously in B and CD4⁺ T cells to control their cell fate dynamics and thus, the character of the antibody response. The remarkable output of this network derives from graded expression, designated by antigen receptor signal strength, of a pivotal transcription factor that regulates alternate cell fate choices.

Keywords: Bcl6; Blimp-1; IRF4; antibody response; cell differentiation; transcription factors.

Figure 1.. Naïve B and CD4⁺ T cell progenitors activate and differentiate into progeny that can act as either effectors, or cells inducing antibody diversification in vertebrates.

Upon antigen specific activation and co-stimulation, B cells can terminally differentiate into effector, antibody secreting plasma cells (PC). Conversely, the B cell can participate in the germinal center and undergo affinity maturation - a process of mutation and selection that modifies the antigen specific BCR repertoire. Likewise, after antigen specific activation and co-stimulation, CD4⁺T cells can terminally differentiate into effector (Teff), pro-inflammatory cytokine secreting cells. Alternatively, the CD4⁺ T cell differentiates into a T follicular helper cell (Tfh), and participates in the germinal center reaction to select high affinity B cells (germinal center B cells: GCB). Not discussed here are progenitor memory cells - long lived cells for rapid reactivation upon a second antigen encounter. However, where memory cells arise in this process remains to be determined.

Figure 2. (Key Figure). Variations in the antibody response by independent control of IRF4 concentrations in B and CD4⁺ T cells.

A) Topology of the IRF4-dependent GRN orchestrating alternative cell fate choice. The network combines an activating connection between the antigen receptor and IRF4 with an incoherent type 1 feedforward edge topology (from IRF4 to Blimp-1/Bcl6). B) Left, Intensity of antigen receptor signaling scales with IRF4 concentrations. Right, dynamics of the type 1 incoherent feedforward motif in regulating alternate cell fate choice as a function of antigen receptor signal intensity / IRF4 concentrations. The architecture of the incoherent motif is predicted to compute fold change detection of IRF4 concentrations to execute alternate cell fate choice by regulation of Blimp-1 or Bcl6. C) During T-dependent antibody responses, independent control of IRF4 concentrations by antigen receptor signal intensity in T and B cells is predicted to result in different outcomes on the quantity and quality of the antibody response. PC: plasma cells; GCB: germinal center B cells; Teff: effector T cell; Tfh: T follicular helper cell.

Figure 3.. Antigen dependent alternate B cell fate decisions.

Antigen recognition induces the expression of IRF4 in naïve B cells. Intensity of BCR and CD40 signaling scale with induced IRF4 concentrations. Higher IRF4 amounts favors the induction of Blimp-1 expression and preferential PC cell fates. Alternatively, lower IRF4 amounts favor the induction of Bcl6 expression and preferential germinal center B cells (GCB) cell fates. Varying IRF4 concentrations affect its partitioning into distinct assemblies of DNA binding partners and DNA recognition elements that are aligned with components of distinct gene programs to effect cell fate choice, including that of Blimp-1 and Bcl6[16]. PC: plasma cells.

Figure 4.. Antigen dependent alternate CD4⁺ T cell fate decisions.

Antigen recognition induces the expression of IRF4. Intensity of TCR signaling and costimulation scale with induced IRF4 concentrations. Higher IRF4 amounts favors the induction of Blimp-1 expression and preferential effector T cell (Teff) cell fates. Alternatively, lower IRF4 amounts favor the induction of Bcl6 expression and preferential follicular helper T (Tfh) cell fates. Varying IRF4 concentrations can affect its partitioning into distinct assemblies of DNA binding partners and DNA recognition elements that are aligned with components of distinct gene programs to effect cell fate choice, including that of Blimp-1 and Bcl6[15].

Figure 5.. Antigen-Dependent Alternate CD4⁺ T-Cell Fate Decisions.

Antigen recognition induces the expression of IRF4. Intensity of TCR signaling and costimulation scale with induced IRF4 concentrations. Higher IRF4 amounts favor the induction of Blimp-1 expression and preferential effector T-cell (Teff) fates. Alternatively, lower IRF4 amounts favor the induction of Bcl6 expression and preferential follicular helper T (Tfh) cell fates. Varying IRF4 concentrations can affect its partitioning into distinct assemblies of DNA-binding partners and DNA recognition elements that are aligned with components of distinct gene programs to effect cell fate choice, including that of Blimp-1 and Bcl6 (15]. Abbreviations: Bcl6, B-cell lymphoma 6; Blimp-1, B lymphocyte-induced maturation protein-1; IRF, interferon regulatory family.