Title | Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Swaims AY, Khani F, Zhang Y, Roberts AI, Devadas S, Shi Y, Rabson AB |
Journal | Blood |
Volume | 116 |
Issue | 16 |
Pagination | 2994-3003 |
Date Published | 2010 Oct 21 |
ISSN | 1528-0020 |
Keywords | Animals, Apoptosis, CD4-Positive T-Lymphocytes, Cell Proliferation, Cytokines, Gene Expression, Gene Products, tax, Mice, Mice, Transgenic, T-Lymphocytes, Helper-Inducer |
Abstract | Infection with the human T-cell leukemia virus-1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia/lymphoma (ATL). Although the pathogenesis of these disorders is poorly understood, it involves complex interactions with the host immune system. Activation of infected T cells may play an important role in disease pathogenesis through induction of the oncogenic HTLV-1 Tax transactivator protein. To test this hypothesis, we employed transgenic mice in which Tax is regulated by the HTLV-1 LTR. T-cell receptor stimulation of LTR-Tax CD4(+) T cells induced Tax expression, hyper-proliferation, and immortalization in culture. The transition to cellular immortalization was accompanied by markedly increased expression of the antiapoptotic gene, mcl-1, previously implicated as important in T-cell survival. Immortalized cells exhibited a CD4(+)CD25(+)CD3(-) phenotype commonly observed in ATL. Engraftment of activated LTR-Tax CD4(+) T cells into NOD/Shi-scid/IL-2Rγ null mice resulted in a leukemia-like phenotype with expansion and tissue infiltration of Tax(+), CD4(+) lymphocytes. We suggest that immune activation of infected CD4(+) T cells plays an important role in the induction of Tax expression, T-cell proliferation, and pathogenesis of ATL in HTLV-1-infected individuals. |
DOI | 10.1182/blood-2009-07-231050 |
Alternate Journal | Blood |
PubMed ID | 20634377 |
Grant List | CA94148 / CA / NCI NIH HHS / United States AI057596 / AI / NIAID NIH HHS / United States DE19413 / DE / NIDCR NIH HHS / United States T32AI007403 / AI / NIAID NIH HHS / United States DE019932 / DE / NIDCR NIH HHS / United States |
Related Faculty:
Francesca Khani, M.D.