T cell lymphomas are a diverse group of tumors found in both dogs and humans, originating from various normal T cell types. Identifying the origin of neoplastic lymphocytes can offer valuable insights into the pathogenesis and clinical behavior of these tumors. T zone lymphoma (TZL) in dogs is characterized by the absence of CD45 expression, a strong breed predilection, and its association with adult-onset demodicosis—a condition believed to be linked to immunosuppression. In this study, our aim was to employ transcriptomic and functional data to determine the normal counterpart of TZL. Identifying the normal counterpart may help us understand both how these tumors arise and explain their clinical behavior. Gene expression profiling using NanoString and RNA seq was used to compare the transcriptome between neoplastic T zone cells, normal canine T cells and publicly available gene sets using Gene Set Enrichment Analysis. Mitogen, anti-CD3 stimulation and PMA/ionomycin stimulation were used to assess T cell proliferation in vitro, and intracellular cytokine production was measured by flow cytometry. Gene expression profiling revealed that TZL is most likely derived from an activated or memory alpha-beta T cell but the cells do not fall cleanly into an effector subtype. TZL cells express CD4-specific transcription factors GATA3 and THPOK, even though TZL cells more commonly express CD8, or neither CD4 nor CD8. TZL cells produce high levels of interferon gamma and tumor necrosis factor alpha when stimulated, further supporting the hypothesis that they are derived from an antigen experienced T cell. TZL cells do not proliferate when stimulated through the T cell receptor but will divide when the T cell receptor is bypassed with PMA and ionomycin. The observation that these cells are derived from a mature, previously activated T cell is the first step in understanding the genesis of this unique T cell tumor.

中文翻译：

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犬 T 区淋巴瘤是一种成熟的、先前激活的 αβ T 细胞的肿瘤

T 细胞淋巴瘤是在狗和人类中发现的一组不同的肿瘤，起源于各种正常 T 细胞类型。识别肿瘤性淋巴细胞的起源可以为了解这些肿瘤的发病机制和临床行为提供有价值的见解。犬的 T 区淋巴瘤 (TZL) 的特点是缺乏 CD45 表达、强烈的品种偏好以及与成年发病的蠕形螨病（一种被认为与免疫抑制有关的疾病）的相关性。在这项研究中，我们的目的是利用转录组和功能数据来确定 TZL 的正常对应物。识别正常的对应物可能有助于我们了解这些肿瘤是如何产生的并解释它们的临床行为。使用 NanoString 和 RNA seq 进行基因表达谱分析，使用基因集富集分析来比较肿瘤性 T 区细胞、正常犬 T 细胞和公开可用的基因集之间的转录组。使用丝裂原、抗CD3刺激和PMA/离子霉素刺激来评估体外T细胞增殖，并通过流式细胞术测量细胞内细胞因子的产生。基因表达谱分析表明，TZL 很可能源自激活的或记忆的 α-β T 细胞，但这些细胞并不能完全归入效应子亚型。TZL 细胞表达 CD4 特异性转录因子 GATA3 和 THPOK，尽管 TZL 细胞更常见地表达 CD8，或者既不表达 CD4 也不表达 CD8。TZL 细胞在受到刺激时会产生高水平的干扰素 γ 和肿瘤坏死因子 α，进一步支持了它们源自经历过抗原的 T 细胞的假设。当通过 T 细胞受体刺激时，TZL 细胞不会增殖，但当 PMA 和离子霉素绕过 T 细胞受体时，TZL 细胞会分裂。观察到这些细胞源自成熟的、先前激活的 T 细胞，这是了解这种独特 T 细胞肿瘤起源的第一步。