Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA.
Department of Pediatrics and Herman B Wells Center for Pediatric Research and.
JCI Insight. 2020 Sep 17;5(18):124465. doi: 10.1172/jci.insight.124465.
Acute graft-versus-host disease (aGVHD) can occur after hematopoietic cell transplant in patients undergoing treatment for hematological malignancies or inborn errors. Although CD4+ T helper (Th) cells play a major role in aGVHD, the mechanisms by which they contribute, particularly within the intestines, have remained elusive. We have identified a potentially novel subset of Th cells that accumulated in the intestines and produced the serine protease granzyme A (GrA). GrA+ Th cells were distinct from other Th lineages and exhibited a noncytolytic phenotype. In vitro, GrA+ Th cells differentiated in the presence of IL-4, IL-6, and IL-21 and were transcriptionally unique from cells cultured with either IL-4 or the IL-6/IL-21 combination alone. In vivo, both STAT3 and STAT6 were required for GrA+ Th cell differentiation and played roles in maintenance of the lineage identity. Importantly, GrA+ Th cells promoted aGVHD-associated morbidity and mortality and contributed to crypt destruction within intestines but were not required for the beneficial graft-versus-leukemia effect. Our data indicate that GrA+ Th cells represent a distinct Th subset and are critical mediators of aGVHD.
急性移植物抗宿主病（aGVHD）可发生在接受造血细胞移植的血液系统恶性肿瘤或先天性错误患者中。虽然 CD4+T 辅助（Th）细胞在 aGVHD 中起主要作用，但它们发挥作用的机制，特别是在肠道内，仍然难以捉摸。我们已经鉴定出一种潜在的新型 Th 细胞亚群，其在肠道中积累并产生丝氨酸蛋白酶颗粒酶 A（GrA）。GrA+Th 细胞与其他 Th 谱系不同，表现出非细胞溶解表型。体外，GrA+Th 细胞在 IL-4、IL-6 和 IL-21 的存在下分化，并且与单独培养 IL-4 或 IL-6/IL-21 组合的细胞在转录上是不同的。在体内，STAT3 和 STAT6 都需要 GrA+Th 细胞分化，并在维持谱系身份中发挥作用。重要的是，GrA+Th 细胞促进 aGVHD 相关发病率和死亡率，并有助于肠道内隐窝破坏，但对移植物抗白血病效应不是必需的。我们的数据表明，GrA+Th 细胞代表一种独特的 Th 细胞亚群，是 aGVHD 的关键介质。
