Abnormally high γδ T cell numbers among individuals with atypical SCID have been reported but detailed immunophenotyping and functional characterization of these expanded γδ T cells are limited. We have previously reported atypical SCID phenotype caused by hypomorphic IL2RG (NM_000206.3) c.172C > T;p.(Pro58Ser) variant. Here, we have further investigated the index patient’s abnormally large γδ T cell population in terms of function and phenotype by studying IL2RG cell surface expression, STAT tyrosine phosphorylation and blast formation in response to interleukin stimulation, immunophenotyping, TCRvγ sequencing, and target cell killing. In contrast to his ⍺β T cells, the patient’s γδ T cells showed normal IL2RG cell surface expression and normal or enhanced IL2RG-mediated signaling. Vδ2 + population was proportionally increased with a preponderance of memory phenotypes and high overall tendency towards perforin expression. The patient’s γδ T cells showed enhanced cytotoxicity towards A549 cancer cells. His TCRvγ repertoire was versatile but sequencing of IL2RG revealed a novel c.534C > A; p.(Phe178Leu) somatic missense variant restricted to γδ T cells. Over time this variant became predominant in γδ T cells, though initially present only in part of them. IL2RG-Pro58Ser/Phe178Leu variant showed higher cell surface expression compared to IL2RG-Pro58Ser variant in stable HEK293 cell lines, suggesting that somatic p.(Phe178Leu) variant may at least partially rescue the pathogenic effect of germline p.(Pro58Ser) variant. In conclusion, our report indicates that expansion of γδ T cells associated with atypical SCID needs further studying and cannot exclusively be deemed as a homeostatic response to low numbers of conventional T cells.

据报道，非典型 SCID 个体中 γδ T 细胞数量异常高，但这些扩增的 γδ T 细胞的详细免疫表型和功能特征有限。我们之前报道过由低效型IL2RG (NM_000206.3) c.172C > T;p.(Pro58Ser) 变体引起的非典型 SCID 表型。在这里，我们通过研究 IL2RG 细胞表面表达、STAT 酪氨酸磷酸化和响应白细胞介素刺激的原始细胞形成、免疫表型、TCRvγ 测序和靶细胞杀伤，进一步研究了指标患者异常大的 γδ T 细胞群的功能和表型。与他的 ⍺β T 细胞相反，患者的 γδ T 细胞显示出正常的 IL2RG 细胞表面表达以及正常或增强的 IL2RG 介导的信号传导。 Vδ2 + 群体随着记忆表型的优势和穿孔素表达的总体趋势成比例地增加。患者的 γδ T 细胞对 A549 癌细胞表现出增强的细胞毒性。他的 TCRvγ 库具有多种用途，但IL2RG测序揭示了一种新的 c.534C > A； p.(Phe178Leu) 体细胞错义变异仅限于 γδ T 细胞。随着时间的推移，这种变异在 γδ T 细胞中变得占主导地位，尽管最初只存在于其中的部分细胞中。在稳定的 HEK293 细胞系中，与 IL2RG-Pro58Ser 变体相比，IL2RG-Pro58Ser/Phe178Leu 变体显示出更高的细胞表面表达，表明体细胞 p.(Phe178Leu) 变体可能至少部分挽救种系 p.(Pro58Ser) 变体的致病作用。总之，我们的报告表明，与非典型 SCID 相关的 γδ T 细胞扩增需要进一步研究，并且不能完全被视为对少量常规 T 细胞的稳态反应。