Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Institute for Advanced Academic Research, Chiba University, Chiba, Japan.
Front Immunol. 2023 Aug 18;14:1211620. doi: 10.3389/fimmu.2023.1211620. eCollection 2023.
Murine IL-17-producing γδT (γδT17) cells are divided into two subsets: natural γδT17 (nγδT17) cells, whose development is restricted to the fetal thymus, and inducible γδT17 cells, which require antigen exposure for their IL-17 production and are presumed to develop from immature γδT17 cells in the adult thymus and whose T cell receptor (TCR) is biased toward Vγ4. Although IL-23 is known to be involved in developing γδT17 cells, the roles of other cytokines, such as IL-21, which is involved in developing Th17 cells like IL-23, in the development, maintenance, and pathophysiology of γδT17 cells remain unknown. Here, we show that IL-21 is dispensable for the fetal thymic development of nγδT17 cells but is required for the peripheral maintenance of Vγ4nγδT17 cells. Upon stimulation with γδTCR, IL-1 plus IL-21 induces the proliferation of Vγ4nγδT17 cells via STAT3 as effectively as IL-1 plus IL-23. Using bone marrow chimeric mice, we demonstrated that immature γδT17 cells are produced in the adult mice from donor adult bone marrow cells and that IL-21 is dispensable for their development. Instead, IL-21 is required to expand newly induced Vγ4γδT17 cells in the periphery upon immunization. Finally, using adoptive transfer experiments of γδT17 cells, we found that IL-21 receptors on γδT17 cells are involved in maintaining Vγ4γδT17 cells, subsequent infiltration of Th17 cells into the spinal cord, and exacerbation of experimental autoimmune encephalomyelitis. Collectively, IL-21 plays a vital role in the maintenance and pathogenesis of Vγ4γδT17 cells.
鼠源白细胞介素-17 产生 γδT（γδT17）细胞分为两个亚群：天然 γδT17（nγδT17）细胞，其发育仅限于胎儿胸腺；诱导型 γδT17 细胞，其白细胞介素-17 的产生需要抗原暴露，被认为是由成人胸腺中的未成熟 γδT17 细胞发育而来，其 T 细胞受体（TCR）偏向于 Vγ4。虽然已知白细胞介素-23 参与了 γδT17 细胞的发育，但其他细胞因子（如白细胞介素-21）的作用，如白细胞介素-23 参与了 Th17 细胞的发育，在 γδT17 细胞的发育、维持和病理生理学中仍不清楚。在这里，我们表明，白细胞介素-21 对于 nγδT17 细胞的胎儿胸腺发育是可有可无的，但对于 Vγ4nγδT17 细胞的外周维持是必需的。在 γδTCR 刺激下，白细胞介素-1 加白细胞介素-21 通过 STAT3 有效地诱导 Vγ4nγδT17 细胞增殖，与白细胞介素-1 加白细胞介素-23 一样有效。使用骨髓嵌合小鼠，我们证明了在成年小鼠中，幼稚 γδT17 细胞是由供体成年骨髓细胞产生的，并且白细胞介素-21 对于它们的发育是可有可无的。相反，在免疫接种时，白细胞介素-21 对于外周新诱导的 Vγ4γδT17 细胞的扩增是必需的。最后，通过 γδT17 细胞的过继转移实验，我们发现 γδT17 细胞上的白细胞介素-21 受体参与维持 Vγ4γδT17 细胞、随后 Th17 细胞浸润脊髓以及实验性自身免疫性脑脊髓炎的恶化。总之，白细胞介素-21 在 Vγ4γδT17 细胞的维持和发病机制中发挥着至关重要的作用。
