Notch signaling represents an important checkpoint between follicular T-helper and canonical T-helper 2 cell fate

Abstract

Type-2 immunity is regulated by two distinct CD4+ T cell subsets. T follicular helper (Tfh) cells are required for humoral hallmarks of type-2 inflammation. T helper type-2 (Th2) cells orchestrate type-2 inflammation in peripheral tissues, such as the lung and intestine. Given the importance of Notch signaling in the establishment of other CD4+ T-helper cell subsets, we investigated whether canonical Notch activation could differentially impact Tfh and Th2 cell fate during the induction of type-2 immunity. These studies show that Tfh cell, but not Th2 cell, generation and function is reliant on Notch signaling. While early Tfh cell specification is influenced by functional Notch ligands on classical dendritic cells, functional Notch ligands on cells other than dendritic cells, T cells, B cells, and follicular dendritic cells are sufficient to achieve full Tfh cell commitment. These findings identify Notch signaling as an early lineage-determining factor between Tfh and Th2 cell fate.

Notch signaling licenses allergic airway inflammation by promoting Th2 cell lymph node egress

“…It was recently shown in a helminth infection model that the Notch1/2 receptors on T cells are required for Tfh generation and IgE class switching, but largely dispensable for Th2 differentiation and lung eosinophilia (29). These results are in apparent contrast with our findings for AAI, as the absence of Notch signaling in T cells -irrespective of a successful Tfh response in the lymph node -abolished both IgE induction and lung eosinophilia.…”

“…Follicular T helper (Tfh) cells promote type 2 immunity and have been postulated as precursors of HDM-specific Th2 cells (26,27). Moreover, Tfh responses rely on Notch signaling (28,29). Indeed, we observed fewer PD-1 + CXCR5 + Tfh cells in the MedLNs of N1N2 ΔCD4/ΔCD4 mice as compared with WT controls (Supplemental Figure 1E).…”

Determination of T Follicular Helper Cell Fate by Dendritic Cells

“…Loss of NOTCH 1 and 2 specifically in CD4 + T cells leads to reduced Tfh cell frequencies, impaired IL-4 production by Tfh cells and concomitantly, reduced GC B cell and IgE responses ( 89 , 90 ). While NOTCH signaling controls IL-4 production by Tfh cells ( 90 ), NOTCH-deficient Tfh cells also fail to downregulate BLIMP1 (PRDM1) or upregulate BCL6, Cmaf, and IL-21, in an IL-4-independent manner ( 89 ). DC-specific deletion of the NOTCH ligand, the E3 ubiquitin ligase Mind bomb1 (MIB1) also impairs early Tfh cell differentiation.…”

“…Tfh cell frequencies in these mice are eventually comparable to controls at later stages of the response indicating that requirement for DC-derived NOTCH signals is not absolute. The authors also demonstrate that depletion of NOTCH ligands on B cells and follicular DCs has no impact on Tfh cell priming ( 90 ).…”

Shaping the diversity of Th2 cell responses in epithelial tissues and its potential for allergy treatment

“…The requirements for IL‐4 production by Tfh cells themselves remain less well understood and differ from those of Th2 cells. Notch signaling has recently been shown to be required for Tfh cell generation but to be dispensable for Th2 cell differentiation in settings of helminth infections, highlighting one bifurcation checkpoint between these two cellular players of type 2 immunity .…”