The emerging role of SETD2 in the regulation of the function of immune cells highlights potential therapeutic strategies for a range of immune diseases. As a key methyltransferase, SETD2 facilitates the trimethylation of lysine 36 on the histone H3 (H3K36ME3), a crucial modification to maintain genomic stability and regulate the transcription of genes. Recent discoveries indicate that SETD2 not only influences tumorigerosis but also plays a pivotal role in the development, differentiation and function of immune cells.
Setd2 involvement in the immune system extends over innate and adaptive immunity. It has proven to be essential in self-renewal and differentiation of hematopoietic stem cells (CSH), maintaining a critical balance for immune homeostasis. The loss of setd2 in CSH can lead to an instability of the genome, increased differentiation to the progenitors and the exhaustion of the CSH. This disturbance not only alters the immune function but also has a risk of malignant transformation.
In the innate immune response, SETD2 has a significant impact on the polarization of macrophages. It inhibits the activation route of M1 macrophages by removing the 1-alpha factor inducted by hypoxia (HIF-1α), thus reducing inflammatory responses. Conversely, the reduced levels of SETD2 are linked to an increased M1 polarization and glycolytic activity, which could exacerbate conditions such as acute pulmonary lesions and osteomyelitis. In addition, it has been shown that the expression of setd2 in mastocytes attenuated systemic mastocytosis, where its loss can cause advanced forms of the disease.
SETD2 also plays an essential role in the adaptive immune system, in particular in the development and function of T lymphocytes. The absence of recombination SETD2 alters the recombination of TCR receptors (TCR), leading to stopping development and lymphopenia of T. In addition, Setd2 influences the balance between the differentiation of TREG cells and TH17, where it promotes the stability of the TREG while removing the pro-inflammatory responses Th17. These regulatory effects are crucial to controlling autoimmune reactions and maintaining immune tolerance.
In the biology of B cells, SETD2 is essential for the rearrangement of the immunoglobulin, crucial for the diversity of antibodies and adaptive immunity. The loss of setd2 leads to a defective recombination of V (d) J, hamper the development of B cells and predisposing cells to lymphomagenesis. In addition, the B cells of the Germinal Center with a reduced SETD2 function have a detection of damage to altered DNA, promoting the progression of B cell lymphoma.
As research progresses, understanding the mechanistic pathways regulated by SETD2 will unlock new possibilities of therapeutic intervention. SETD2 targeting could potentially modulate the functions of immune cells, offering new treatments for autoimmune diseases, inflammatory conditions and hematological malignant tumors.