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

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.