IL21, Interleukin-21, is a cytokine that plays a crucial role in the immune system. Produced mainly by CD4 T cells, especially those associated with follicular helper cells (TFH), it promotes effector functions and memory differentiation of CD8 T cells, and is involved in the germinal center reaction, thus being important for generating immunological memory [2,5]. It exerts its effects through the IL-21R-γc signaling complex [5].

In the context of natural killer (NK) cell expansion, using feeder cells expressing membrane-bound (mb) IL21 alone drives superior yield compared to mbIL15, while mbIL15 alone drives superior functionality. However, sequential exposure to mbIL21 followed by mbIL15 optimizes both yield and function of NK cells [1]. In autoimmune diseases, elevated IL21 is commonly found in patients' tissues and/or sera. In shoulder arthritis, IL21 inhibits miR-361-5p, promoting MAP3K9 and aggravating the disease progression [3]. In cancer immunotherapy, IL21 produced by tumor-associated T follicular helper cells and hyperactivated/exhausted CXCL13+CD4+ T cells in the tumor microenvironment, synergizes with anti-PD-1 blockade. It drives tumor antigen-specific CD8+ T cells to clonal expand and differentiate, and promotes dendritic cell activation and monocyte to M1 macrophage differentiation [4].

In conclusion, IL21 is a key cytokine in the immune system, with diverse functions in NK cell expansion, autoimmune diseases, and cancer immunotherapy. Studies on its role, especially through models like sequential cytokine exposure in NK cell expansion and its implications in disease conditions, have provided valuable insights into immune-related biological processes and potential therapeutic strategies.