Instructing T_H1/T_H2-cell differentiation

According to a new study reported in Cell, the development of T helper 2 (T_H2) cells is not just a default pathway that occurs in the absence of T_H1-cell-inducing signals but is an instructive process determined by Notch ligands.

Naive T cells develop into polarized effector cells that mediate effective immune responses. T_H1 cells are important for cellular immunity and are characterized by the production of interferon-γ (IFN-γ), whereas T_H2 cells are important for humoral immunity and produce the cytokines interleukin-4 (IL-4), IL-5 and IL-13.

IL-12 produced by antigen-presenting cells (APCs) can drive T_H1-cell differentiation, but in the absence of IL-12, T cells do not neccesarily develop along a default pathway into T_H2 cells, indicating that instructive factors for T_H2-cell differentiation exist. IL-4 is important for T_H2-cell induction, but the fact that T_H2 cells can develop in the absence of IL-4 signalling (in signal transducer and activator of transcription 6 (STAT6)-deficient mice) indicates that other T_H2-promoting signals exist.

This study explored the factors that are responsible for T_H2-cell differentiation. Notch receptors are known to be involved in cell-fate decisions, and the DNA-binding factor RBPJ-κ is a key component of Notch-signalling pathways. Because RBPJ-κ is expressed at a low level in naive CD4⁺ T cells but is preferentially expressed by T_H2 cells, the authors proposed that the Notch-signalling pathway might regulate T-cell differentiation.

Notch ligands belong to two main families — Jagged and Delta. Assessment of ligand expression revealed that the ability of dendritic cells to induce T_H2-type responses correlated with Jagged-1 expression, and the ability to induce T_H1-type responses correlated with Delta-4 expression. APCs expressing Jagged-1 were able to induce T_H2-cell differentiation of T cells from STAT6-deficient mice, indicating that induction is independent of IL-4–STAT6 signalling. Further experiments showed that ligation of Notch instructs T_H2-cell differentiation by inducing the transcription factor GATA3 and by directly regulating transcription of the gene encoding IL-4 through targeting RBPJ-κ sites in a 3′ enhancer region.

This study challenges the dogma that the development of T_H2 cells is a default pathway that occurs in the absence of T_H1-cell-inducing signals. The molecular mechanisms controlling Delta-4-mediated induction of T_H1-cell differentiation remain undefined, and further studies will be required to determine how Delta and Jagged can mediate such different responses by engaging Notch receptors.