Journal
ONCOIMMUNOLOGY
Volume 11, Issue 1, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2021.2015170
Keywords
CTLA4; CD28; murine model; ATLL; AITL; fusion gene
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Funding
- National Research Foundation of Korea - Ministry of Science and ICT, Republic of Korea [NRF-2015K1A4A3047851, NRF-2020R1A2C2099719, NRF-2019R1F1A1062011]
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The CTLA4-CD28 gene fusion occurs in various types of T cell lymphoma, and it can convert inhibitory signals to activating signals, promoting T cell proliferation and transformation. A murine model expressing this fusion gene specifically in T cells showed shorter lifespans, inflammatory responses, and higher levels of T cell activation and infiltration in various organs. The gene expression pattern in CD4+ T cells in this model resembled that of ATLL and AITL tissues.
CTLA4-CD28 gene fusion has been reported to occur in diverse types of T cell lymphoma. The fusion event is expected to convert inhibitory signals to activating signals and promote proliferation and potentially transformation of T cells. To test the function of the CTLA4-CD28 fusion gene in vivo, we generated a murine model that expresses the gene in a T cell-specific manner. The transgenic mice have shorter life spans and display inflammatory responses including lymphadenopathy and splenomegaly. T cells in turn show higher levels of activation and infiltrate various organs including the lung and skin. T cells, in particular CD4+ helper T cells, were also readily transplantable to immunocompromised mice. Transcriptomic profiling revealed that the gene expression pattern in CD4 + T cells closely resembles that of adult T cell leukemia/lymphoma (ATLL) and that of angioimmunoblastic T cell lymphoma (AITL) tissues. Consistently, we detected supernumerary FOXP3+ cells and PD-1+ cells in transgenic and transplanted mice. This is the first report demonstrating the transforming activity of the CTLA4-CD28 fusion gene in vivo, and this murine model should be useful in dissecting the molecular events downstream to this mutation.
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