Notch and GATA3 Join Forces Negative MAML1 Or Lacking RBP-J

R e s e a r ch highlights

DOI: 10.1038/nri2167

T cells expressing an activated allele T c e l l s of Notch ICD and was downregu- lated in T cells expressing dominant- Notch and GATA3 join forces negative MAML1 or lacking RBP-J. Importantly, Notch induced Gata3 expression even in cells lacking Notch and GATA3 (GATA-bind- Notch has been implicated in periph- STAT6 (signal transducer and ing protein 3) are well known as eral T-cell differentiation, but no con- activator of transcription 6), which is master regulators of intrathymic sensus on this had been reached. Both known to drive Gata3 transcription T-lineage fate determination and Amsen et al. and Fang et al. therefore induced by IL-4 receptor signalling.

T helper 2 (TH2)-cell differentiation, took a direct approach to investigate Further analysis revealed that, of the respectively, but never before have how Notch might be involved in two promoters that are known to they been functionally linked. Now, T-cell differentiation. Signalling by control Gata3 gene expression, Notch two studies in Immunity report Notch is initiated by ligand binding preferentially targets the upstream that Notch directly regulates Gata3 to its extracellular region, followed one, through a conserved binding site expression, and together they ensure by proteolytic cleavage to release its for RBP-J.

optimal TH2-cell differentiation. intracellular domain (ICD). The ICD To prove that the ability of Notch Besides its clear role in the thymus, then translocates to the nucleus and to induce IL-4 production and

forms a complex with the DNA-bind- TH2-cell responses requires GATA3, ing protein recombination-signal- studies using T cells lacking GATA3 binding protein-J (RBP-J; also known or expressing a dominant-negative as CSL), to which Mastermind-like 1 form of GATA3 were performed. (MAML1) and other co-activators Forced expression of Notch ICD are recruited, resulting in a tran- in these cells failed to increase IL-4

scriptional activator complex. Both production under TH2-cell polarizing groups observed that abrogation of conditions and instead led to a strong

Notch signalling in peripheral T cells, induction of the TH1-cell cytokine either by deleting Notch1 and Notch2, interferon-γ, indicating that GATA3 by deleting Rbpj or by expressing a is indeed crucial for Notch-mediated

dominant-negative form of MAML1, TH2-cell responses. Fang et al. also

prevented the production of the TH2- showed that Notch and GATA3 syn- cell-derived cytokine interleukin-4 ergize to promote IL-4 production (IL-4). Moreover, Amsen et al. con- and that their effect was independent firmed previous studies showing that of STAT6 and any further positive

the robust TH2-cell response normally feedback from IL-4. induced by the injection of parasite So, these studies confirm an

antigens did not occur in mice with important role for Notch in TH2- Notch-signalling-deficient peripheral cell differentiation, through direct T cells. regulation of Gata3 expression. Given that GATA3 is a key Lucy Bird

regulator of TH2-cell differentiation, ORIGINAL RESEARCH PAPERS through its ability to drive epigenetic Amsen, D. et al. Direct regulation of modification of the Il4 locus, both Gata3 expression determines the T helper differentiation potential of Notch. Immunity groups examined whether Notch 27, 89–99 (2007) | Fang, T. C. et al. Notch directly

ck regulates Gata3 expression during T helper 2 cell

o induces the TH2-cell response by t differentiation. Immunity 27, 100–110 (2007) s directly targeting Gata3. Indeed, FURTHER READING Kubo, M. Notch: filling a compared with control cells, Gata3 hole in T helper 2 cell differentiation. Immunity

anana + 27, 3–5 (2007) b expression was upregulated in CD4