{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nInterleukin‐21 (IL‑21) is a type I cytokine produced primarily by activated CD4⁺ T cells—including follicular helper T cells—that exerts pleiotropic effects on the adaptive immune system. IL‑21 is a critical regulator of humoral immunity, promoting B cell proliferation, class‐switch recombination, and plasma cell differentiation. In the presence of costimulatory signals such as CD40 ligand, IL‑21 induces key transcription factors (e.g. BLIMP‑1) while also modulating factors like Bcl‑6, thereby guiding the transition from activated B cells to antibody‐secreting cells and sustaining long‐lived memory responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its B cell–directed actions, IL‑21 is deeply implicated in the differentiation and function of T cell subsets and in the genetic predisposition to autoimmune diseases. Along with transforming growth factor‑β, IL‑21 can drive the development of human T helper 17 cells, and it is instrumental in expanding T peripheral helper cells that support autoreactive B cell responses in disorders such as systemic lupus erythematosus and rheumatoid arthritis. Genetic studies have linked variations in the IL2/IL21 locus with conditions including alopecia areata, celiac disease, and inflammatory bowel disease, reinforcing its multifaceted role in autoimmunity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIL‑21 also modulates innate immunity and is being exploited for immunotherapeutic applications. Studies using genetically engineered antigen‐presenting cells expressing membrane‐bound IL‑21 demonstrate its impressive capacity to expand natural killer (NK) cells with enhanced telomere lengths, while in cooperation with IL‑15 it promotes interferon‑γ production by NK and T cells. In the tumor microenvironment, IL‑21 has been shown to contribute to a pivotal Tfh/B cell axis favoring improved survival in colorectal cancer, and it enhances the generation of high‐affinity cytotoxic T lymphocytes in chronic viral infections. In other malignant settings—such as chronic lymphocytic leukemia—the combination of IL‑21 with CD40 ligand drives leukemic cell proliferation and differentiation, and similarly, its incorporation into adoptive T cell immunotherapy protocols bolsters the formation of durable memory phenotypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, IL‑21 functions within complex regulatory networks by interacting with other cytokines and signaling pathways. It can induce IL‑10 production—thereby exerting immunosuppressive effects—and, by triggering IL‑22 production through STAT3‐dependent epigenetic remodeling, it helps fine‑tune mucosal immunity. Moreover, IL‑21 and its receptor are expressed by epithelial cells in the gut, where its dysregulation is linked to inflammatory bowel disease, and its increased expression is observed in IgG4‑related disorders and psoriasis. Collectively, these interactions—with factors such as IL‑27, TGF‑β, and costimulatory molecules—not only influence the balance between pro‑inflammatory and regulatory responses in infections and autoimmunity but also affect tumor progression and therapeutic outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Warren J Leonard, Rosanne Spolski "}, {"type": "b", "children": [{"type": "t", "text": "Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Rev Immunol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nri1688"}], "href": "https://doi.org/10.1038/nri1688"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16138102"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16138102"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Katsutoshi Ozaki, Rosanne Spolski, Rachel Ettinger, et al. 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