Take two for Notch

Previous studies have indicated that signalling through Notch proteins is involved in the differentiation of CD4⁺ T cells into T helper (T_H) cells, although whether these signals are required for differentiation into T_H1 cells, T_H2 cells or both was not clear. But now, in a paper published in The Journal of Experimental Medicine, Notch signalling in mature CD4⁺ T cells is shown to be required for T_H2-cell-mediated immunity.

Notch signalling that depends on the transcription factor CSL (also known as RBP-Jκ) requires the transcription cofactor mastermind-like 1 (MAML1). So, to study the role of Notch signalling in CD4⁺ T cells, Tu et al. generated mice (denoted as CCD mice) in which a green-fluorescent-protein-tagged, dominant-negative form of MAML1 was expressed only by CD4⁺ T cells. Importantly, T-cell development — in terms of the cellularity of the thymus, the proportion of CD4⁺ and CD8⁺ T cells, and the expression of cell-surface markers of activation — was normal in these mice. However, when CD4⁺ T cells from these mice were cultured under T_H2-cell-polarizing conditions, the proportion of cells that produced interleukin-4 (IL-4), and the amount of IL-4 that they produced, was markedly lower than in control-cell cultures. By contrast, normal numbers of interferon-γ-producing cells were generated after culture under T_H1-cell-polarizing conditions.

Consistent with a role for CSL-dependent Notch signalling in optimal differentiation into T_H2 cells, CCD mice failed to generate a protective T_H2-cell response after infection with Trichuris muris. By contrast, CCD mice infected with Leishmania major generated a protective T_H1-cell response similar to that generated by control animals.

This study indicates that CSL-dependent Notch signalling is required for generation of a protective T_H2-cell response in vivo. The authors suggest that targeting this signalling pathway could potentially be used to treat T_H2-cell-mediated diseases such as asthma.