Mutation of inhibitory helix-loop-helix protein Id3 causes γδ T-cell lymphoma in mice

Abstract

Human γδ T-cell lymphoma is a rare clinicopathologic entity with aggressive course and poor prognosis. The etiology and pathogenesis of γδ T-cell lymphoma is unknown. We show here that mice with deficiency in inhibitory helix-loop-helix protein Id3 (Id3^−/−) developed γδ T-cell lymphoma that resembled human γδ T-cell lymphoma. The Id3^−/− mice with lymphoma showed splenomegaly, hepatomegaly, and lymphadenopathy with involvement of bone marrow, thymus, kidney, and lungs between 6 and 15 months of age. Phenotypic analysis revealed that lymphomatous cells were cluster of differentiation (CD)3⁺, γδ T-cell receptor (TCR)⁺, and αβ TCR⁻, and expressed CD8⁺CD4⁻, CD4⁺CD8⁻, or a mixture of the two. Id3^−/− γδ T-cell lymphoma used predominantly Vγ1.1, some Vγ3, yet no Vγ2 TCR, and some showed increased levels of the oncogene c-Myc. Strikingly, adoptive transfer of the γδ T-cell lymphoma into syngeneic Rag1^−/− mice resulted in aggressive γδ T-cell lymphoma, identical to the Id3^−/− donor. Thus, our data demonstrate that Id3 regulates the development of γδ T-cell lymphoma in mice, raising a possibility of Id3 gene mutation in human γδ T-cell lymphoma. Our model will provide a tool for studying the molecular mechanisms and development of human γδ T-cell lymphoma.