CD38+ NK cells: novel players in immunoregulation

CD38 is a transmembrane protein and ectoenzyme that mainly degrades nicotinamide adenine dinucleotide (NAD⁺). Studies have revealed increased numbers of CD38-expressing NK (CD3-CD38+CD56+) cells in many diseases. CD38+ NK cell proportions in the peripheral blood and synovial fluid are increased in patients with rheumatoid arthritis (RA), and these cells produce high levels of interferon-γ (IFN-γ) and low levels of transforming growth factor-β (TGF-β), suppressing the differentiation of CD4+ T cells to regulatory T cells (Tregs) to disrupt immune tolerance. CD38+ NK cell proportions in the peripheral blood and tumor tissues are also increased in patients with colorectal cancer (CRC). However, CD38+ NK cells produce low levels of IFN-γ and NAD⁺ and high levels of TGF-β and adenosine (ADO) and can promote Treg differentiation and macrophage polarization to tumor-associated macrophages (TAMs) to interrupt immune surveillance. CD38+ NK cells were not detected in CD38-KO tumor-bearing mice, and their xenograft tumors grew slowly. Furthermore, the expression of heat shock 70-kDa protein 1B (HSPA1B), a known tumor suppressor, was decreased in CD38+ NK cells from CRC patients but increased in the NK subset from RA patients. HSPA1B can suppress the signaling activity of NF-κB, a regulator of proinflammatory cytokine production. CD38 and CD16 cooperate on the NK cell membrane; most CD38+ NK cells are CD38+CD16+ NK cells that can suppress Treg differentiation. The proportion of CD38+CD16- NK cells among CD38+ NK cells in the peripheral blood was increased in patients with CRC or other tumors. The above results suggest that CD38+CD16+ and CD38+CD16- NK cells have opposing regulatory effects on CD16, HSPA1B and NF-κB signaling and cytokine secretion, leading to opposing effects on immune balance. This review provides a reference for understanding disrupted immune tolerance and surveillance, though the evidence is preliminary.