Department of Immunology, Second Faculty of Medicine, Charles University and University Hospital Motol, V Uvalu 84, 150 06, Prague, Czech Republic.
Department of Paediatric and Adult Rheumatology, University Hospital Motol, Prague, Czech Republic.
J Clin Immunol. 2022 Feb;42(2):274-285. doi: 10.1007/s10875-021-01154-9. Epub 2021 Oct 29.
22q11.2 deletion syndrome (22q11.2DS) is a primary immunodeficiency characterized chiefly by the hypoplasia of the thymus resulting in T cell lymphopenia, increased susceptibility to infections, and higher risk of autoimmune diseases. The irregular thymic niche of T cell development may contribute to autoimmune and atopic complications, whereas the compensatory mechanism of homeostatic T cell proliferation and continuous immune stimulation may result in T cell senescence and exhaustion, further aggravating the immune system dysregulation.
We used flow cytometry to investigate T cell maturation, delineation, proliferation, activation, and expression of senescence and exhaustion-associated markers (PD1, KLRG1, CD57) in 17 pediatric and adolescent patients with 22q11.2DS and age-matched healthy donors.
22q11.2DS patients aged 0-5 years had fewer naïve but more effector memory T cells with a tendency to approach normal values with increasing age. Young patients in particular had a higher percentage of proliferating T cells and increased expression of PD1, KLRG1, and CD57, as well as cells co-expressing several exhaustion-associated molecules (PD1, KLRG1, Tbet, Eomes, Helios). Additionally, high-risk 22q11.2DS patients with very low numbers of CD4 T cells had significantly higher percentage of Th1 and Th17 T cells, driven in part by higher proportion of mature T cell forms.
The low thymic output and accelerated T cell differentiation remain the principal features of 22q11.2DS patient immunity, especially in young patients of < 5 years. Later in life, homeostatic proliferation drives expression of T cell exhaustion and senescence-associated markers, suggesting functional aberrations in addition to numeric T cell deficiency.
22q11.2 缺失综合征（22q11.2DS）是一种主要的免疫缺陷症，其特征主要为胸腺发育不全导致 T 细胞淋巴细胞减少症，增加了感染易感性和自身免疫性疾病的风险。T 细胞发育的非规则胸腺生态位可能导致自身免疫和特应性并发症，而稳态 T 细胞增殖和持续免疫刺激的代偿机制可能导致 T 细胞衰老和衰竭，进一步加重免疫系统失调。
我们使用流式细胞术检测了 17 例儿科和青少年 22q11.2DS 患者和年龄匹配的健康供体的 T 细胞成熟、分化、增殖、激活以及衰老和衰竭相关标志物（PD1、KLRG1、CD57）的表达。
0-5 岁的 22q11.2DS 患者幼稚 T 细胞较少，但效应记忆 T 细胞较多，且随着年龄的增长有接近正常的趋势。尤其是年轻患者的增殖 T 细胞比例更高，PD1、KLRG1 和 CD57 的表达增加，以及同时表达几种衰竭相关分子（PD1、KLRG1、Tbet、Eomes、Helios）的细胞比例也增加。此外，CD4 T 细胞数量极低的高危 22q11.2DS 患者的 Th1 和 Th17 T 细胞比例明显更高，部分原因是成熟 T 细胞形式的比例较高。
低胸腺输出和加速的 T 细胞分化仍然是 22q11.2DS 患者免疫的主要特征，尤其是在年龄<5 岁的年轻患者中。在以后的生活中，稳态增殖会导致 T 细胞衰竭和衰老相关标志物的表达，这表明除了 T 细胞数量不足外，还存在功能异常。
