A new mechanism of ILC2 immune cell development may be related to the exacerbation of allergic diseases

A new mechanism of ILC2 immune cell development may be related to the exacerbation of allergic diseases

Scientists have identified a G3SE-dependent mechanism for ILC2 development. Source: Yosuke Toda and Arifumi Iwata from Chiba University

Overproduction of group 2 innate lymphoid cells, or ILC2s—a type of white blood cell—can sometimes exacerbate conditions such as asthma, chronic sinusitis, atopic dermatitis, and organ fibrosis by exaggerating the immune response. Although there are immunomodulatory drugs that can suppress T helper type 2 (Th2) cells, there is currently a lack of drugs that can suppress ILC2s.

But now, researchers led by assistant professor Arifumi Iwata of Chiba University Hospital in Japan have identified molecular processes key to ILC2 maturation in a groundbreaking study that could lead to the development of a new therapeutic strategy targeting ILC2s.

“Although it is clear that Th2 and ILC2 cells play key roles in allergic diseases, the mechanisms of Th2 differentiation and ILC2 development in vivo have been largely unknown,” says Dr. Iwata, explaining the logic behind the study. Along with Dr. Iwata, Hiroki Furuya, Yosuke Toda, and Hiroshi Nakajima, all from the Graduate School of Medicine at Chiba University, participated in the study published in Nature communication on July 5, 2024

“Since allergic diseases may worsen after discontinuation of current drugs that inhibit type 2 cytokines, we undertook this study to elucidate and control the upstream regulation of type 2 cytokine production, i.e., in vivo Th2 cell differentiation and ILC2 development mechanisms, which we believe are important issues in controlling allergic diseases,” adds Dr. Iwata, explaining the details of their study.

Tandem GATA3-related super-enhancers are essential for peripheral ILC2 development. Source: Nature communication (2024). DOI: 10.1038/s41467-024-49881-y

All white cells originate from “precursor cells,” which are cells capable of differentiating into B cells, T cells, and innate lymphoid cells (ILCs), including ILC2s. GATA3, a protein produced by the GATA3 gene in humans, is crucial for the proper conversion of precursor cells into ILC2s.

In this study, the research team discovered that regulatory regions in the genome located 500–764 kb downstream of Gata3, called GATA3-associated tandem super-enhancers or G3SE, are responsible for upregulating GATA3 in the bone marrow, which further leads to the transformation of precursor cells into ILC2s.

Using genetically modified G3SE-deficient mice and methods such as single-cell RNA sequencing and flow cytometry, they discovered that the mechanism of GATA3 induction is crucial for late-stage ILC2 production. Because the mice lack G3SE, GATA3 levels did not increase sufficiently during this stage of precursor maturation, and as a result, the researchers found that G3SE-deficient mice had significantly low levels of ILC2.

“We discovered a novel late stage of ILC2-committed precursors in ILC2 differentiation. We also found that induction of GATA3 expression by ILC2-specific GATA3 super-enhancers is essential for the differentiation of late ILC2-committed precursors into mature ILC2s,” says Dr. Iwata.

However, by comparing cells from wild-type and G3SE-deficient mice, the researchers found that increasing GATA3 induces ILC2 differentiation via an intermediate step in which levels of a protein called CNOT6L increase. Therefore, targeting the gene that makes this protein can reduce the levels of ILC2 in the body. These results suggest that in the future, gene therapies targeting CNOT6L could help bypass the exaggerated immune responses caused by ILC2s, helping to treat a range of diseases.

“Although these findings are not directly life-changing for patients, further elucidation of the ILC2-specific differentiation mechanism and elaboration of the regulatory mechanisms identified in this study may aid in the development of novel and curative therapies for refractory allergic disease pathologies,” concluded Dr. Iwata.

More information:
Hiroki Furuya et al., Stage-specific GATA3 induction promotes ILC2 development after lineage establishment, Nature communication (2024). DOI: 10.1038/s41467-024-49881-y

Provided by Chiba University

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