What question did this study set out to answer?

The study aims to explore the origin of canine intestinal T-cell lymphoma from intraepithelial lymphocyte subsets associated with chronic enteropathy.

April 1, 2026

Comprehensive phenotypic and clonality analysis of intraepithelial lymphocytes of intestinal T-cell lymphoma and chronic enteropathy in dogs

Key Points

The study aims to explore the origin of canine intestinal T-cell lymphoma from intraepithelial lymphocyte subsets associated with chronic enteropathy.
Flow cytometry and immunohistochemistry on biopsy samples from 62 dogs
Evaluation of IEL phenotypes including CD4 and CD8α markers
RNA in situ hybridization to detect NKp46 expression
Clonality analysis of isolated IELs
ITCLs predominantly exhibited a CD4−CD8α− immunophenotype.
Increased forward scatter values in IELs correlated with higher Ki-67 indices suggesting proliferation.
Clonality peaks were found in various patient groups but limited diagnostic differentiation between ITCL and CE was observed.
Most CE cases had low NKp46 positivity, complicating the understanding of IEL behavior in lymphoma.

Abstract

Canine intestinal T-cell lymphoma (ITCL) may arise from intraepithelial lymphocyte (IEL) subsets expanded in chronic enteropathy (CE). To investigate this potential cell of origin, we performed flow cytometry, immunohistochemistry, and RNA in situ hybridization on IELs using biopsy samples from 62 dogs, including 6 large-cell lymphomas (LCLs), 9 small-cell lymphomas (SCLs), 31 CEs with increased IELs (IEL + CE), and 16 CEs without increased IELs (IEL – CE). IELs in ITCLs were predominantly CD4 − CD8α − (LCL, 5/6; SCL, 4/9), and 4/31 IEL + CEs had a higher proportion of CD4 − CD8α − IELs than the other CE cases. Forward scatter values of CD4 − CD8α − IELs were higher in IEL + CEs compared with IEL – CEs, correlating positively with the Ki-67 index, indicating proliferation of this population. An increase in IELs lacking T-cell receptor expression was observed in 1/4 LCL, 2/5 SCL, and 1/13 IEL + CE cases. Lack of surface CD3 was observed in 2/9 SCL cases. One of 5 LCL cases partially expressed NKp46, whereas the proportion of NKp46 + IELs was low (< 4%) in 32/33 CE cases examined. In addition, 3/6 LCL cases expressed NKp46 mRNA without detectable protein expression. Clonality analysis of isolated IELs yielded at least 1 clonal peak in 1/2 LCLs, 4/7 SCLs, 12/23 IEL + CEs, and 4/13 IEL – CEs, underscoring the limited diagnostic utility on distinguishing ITCL, particularly SCL, from IEL + CE. These findings suggest that most canine ITCLs have a CD4 − CD8α − immunophenotype and that unconventional IELs in IEL + CE may be the cells of origin. Moreover, the distinction between ITCL and CE remains challenging, emphasizing the importance of integrated diagnostic approaches.

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