The different faces of Notch in T-helper-cell differentiation

Interleukin-12 (IL-12) and IL-4 induce T helper 1 (T(H)1)- and T(H)2-cell differentiation, respectively, in vitro. However, not all T(H)1-cell responses require IL-12 in vivo, and T(H)2-cell responses are remarkably independent of IL-4-receptor signalling, suggesting that other polarizing signals must exist. Accumulating evidence indicates that Notch is a candidate receptor that might mediate these signals. However, contrasting roles for Notch have been proposed: some evidence shows that Notch promotes T(H)1-cell differentiation, whereas other evidence supports a prominent role for Notch in T(H)2-cell differentiation. In this Review, we discuss recent findings that help to reconcile this discrepancy and highlight the accumulating evidence for the role of Notch in T-cell-mediated diseases.