IL-21: From Tfh Cell Effector Molecule to Key Driver of Autoimmune Diseases

The functional regulation of CD8+ T cells by IL-21 is highly context-dependent. TCR stimulation signals not only induce IL-21 production but also promote IL-21R expression, enhancing proliferation and the release of effector molecules such as IFN-γ. However, in the absence of TCR stimulation, IL-21 induces CD8+ T cell anergy. IL-21 promotes the differentiation of CD4+ T cells into Tfh and Th17 cells and stimulates CD8+ T cells to produce IL-17. IL-21/IL-21R signaling facilitates the formation of tissue-resident CD8+ memory T cells (CD69hi CD103+), a mechanism involving the Prdm1 gene—a downstream target gene of the IL-21R signaling pathway that encodes the Blimp1 protein. Blimp1 binds to loci such as S1pr1, Ccr7, and Tcf7 to suppress their expression, preventing cell egress from tissues. Tissue-resident memory T cells are one of the drivers of autoimmune diseases. Another notable feature of IL-21/IL-21R signaling in CD8+ T cells is its ability to prevent terminal exhaustion during repeated TCR stimulation, likely by reducing glycolysis and increasing fatty acid oxidation. Combining IL-21R agonists with PD-1 antibodies has emerged as an effective strategy for tumor treatment.

IL-21 plays a critical pathological driving role in multiple autoimmune diseases. In systemic lupus erythematosus, IL-21 secreted by Tph cells promotes B cell differentiation into plasmablasts, which secrete autoantibodies and drive SLE progression. In rheumatoid arthritis, IL-21 secreted by Tph cells not only promotes B cell differentiation into plasma cells but also acts on osteoclasts, fibroblast-like synoviocytes, synovial macrophages, and CD8+ T cells—approximately 80% of CD8+ T cells in the synovial fluid of RA patients are IL-21R-positive, compared to less than 40% in other forms of arthritis and healthy controls. These cells contribute to joint destruction and inflammation. In juvenile idiopathic arthritis, IL-21 is the most elevated cytokine in patient serum, with 20% of CD4+ T cells in synovial fluid producing IL-21, which also secrete IFN-γ and TNF-α. In type 1 diabetes, IL-21 is primarily secreted by Tfh cells, promoting B cell differentiation into plasma cells that produce autoantibodies targeting β cells. In psoriasis, IL-21 expression is elevated, mainly secreted by CD4+ T cells and NKT cells, with IL-21R present in skin T cells, B cells, NK cells, and keratinocytes. In Sjögren's syndrome, Tfh cells and tissue-resident memory T cells are involved in disease pathogenesis, with autoantibodies and a high proportion of B cells in salivary glands consistent with aberrant IL-21 signaling. Additionally, IL-21 contributes to the pathogenesis of vitiligo, antiphospholipid syndrome, pemphigus, and giant cell arteritis. In vitiligo, the affected areas are primarily populated by CD8+ TRM (CD69hi CD103hi CXCR3+), with minimal involvement of CD4+ T cells. In antiphospholipid syndrome, IL-21 primarily acts on B cells rather than CD8+ T cells. In pemphigus, IL-21 exerts its effects through B cells and CD8+ T cells. In giant cell arteritis, IL-21 secreted by CD4+ T cells participates in disease pathogenesis via Th1, Th17, and CD8+ TRM cells.

As a key effector secreted by Tfh, Tph, and Th17 cells, IL-21 plays an irreplaceable dual role in autoimmune diseases and tumor immunology due to its broad regulatory capabilities on CD8+ T cells, CD4+ T cells, and B cells. Its pathological driving role in ten autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis, positions it as a highly promising therapeutic target in the field of autoimmune disease treatment. IL-21 Protein, Human provides critical tool support for in-depth analysis of the IL-21 signaling network and its functions in autoimmune diseases.

In IL-21-related basic research and drug development, high-quality human IL-21 recombinant protein is a core tool for signal pathway analysis, immune cell function studies, and drug activity evaluation. To meet this research demand, UniLove offers IL-21 Protein, Human, suitable for IL-21/IL-21R binding activity analysis, JAK-STAT signaling pathway mechanism exploration, and in vitro screening and evaluation of IL-21-targeting antibody drugs.