New insights into how SETD2 shapes immunity and disease

The emerging role of SETD2 in regulating immune cell function is shedding light on potential therapeutic strategies for a range of immune-related diseases. As a key methyltransferase, SETD2 facilitates the trimethylation of lysine 36 on histone H3 (H3K36me3), a modification crucial for maintaining genomic stability and regulating gene transcription. Recent discoveries indicate that SETD2 not only influences tumorigenesis but also plays a pivotal role in the development, differentiation, and function of immune cells.

SETD2's involvement in the immune system spans across both innate and adaptive immunity. It has been found to be essential in the self-renewal and differentiation of hematopoietic stem cells (HSCs), maintaining a balance critical for immune homeostasis. The loss of SETD2 in HSCs can lead to genome instability, increased differentiation towards progenitors, and HSC exhaustion. This disruption not only impairs immune function but also poses a risk of malignant transformation.

Within the innate immune response, SETD2 has a significant impact on macrophage polarization. It inhibits the M1 macrophage activation pathway by suppressing hypoxia-inducible factor 1-alpha (HIF-1α), thereby reducing inflammatory responses. Conversely, reduced levels of SETD2 are linked to increased M1 polarization and glycolytic activity, which could exacerbate conditions like acute lung injury and osteomyelitis. Furthermore, SETD2 expression in mast cells has been shown to mitigate systemic mastocytosis, where its loss can lead to advanced forms of the disease.

SETD2 also plays a critical role in the adaptive immune system, particularly within T cell development and function. The absence of SETD2 impairs T cell receptor (TCR) recombination, leading to developmental arrest and T cell lymphopenia. Additionally, SETD2 influences the balance between Treg and Th17 cell differentiation, where it promotes Treg stability while suppressing pro-inflammatory Th17 responses. Such regulatory effects are crucial for controlling autoimmune reactions and maintaining immune tolerance.

In B cell biology, SETD2 is indispensable for immunoglobulin gene rearrangement, crucial for antibody diversity and adaptive immunity. Loss of SETD2 leads to defective V(D)J recombination, hampering B cell development and predisposing cells to lymphomagenesis. Moreover, germinal center B cells with reduced SETD2 function exhibit impaired DNA damage sensing, promoting B-cell lymphoma progression.

As research advances, understanding the mechanistic pathways regulated by SETD2 will unlock new possibilities for therapeutic intervention. Targeting SETD2 could potentially modulate immune cell functions, offering novel treatments for autoimmune diseases, inflammatory conditions, and hematological malignancies.