HTLV-1 propels untransformed CD4+ lymphocytes into the cell cycle while protecting CD8+ cells from death
David Sibon, Anne-Sophie Gabet, Marc Zandecki, Christiane Pinatel, Julien Thête, Marie-Hélène Delfau-Larue, Samira Rabaaoui, Antoine Gessain, Olivier Gout, Steven Jacobson, Franck Mortreux, Eric Wattel
David Sibon, Anne-Sophie Gabet, Marc Zandecki, Christiane Pinatel, Julien Thête, Marie-Hélène Delfau-Larue, Samira Rabaaoui, Antoine Gessain, Olivier Gout, Steven Jacobson, Franck Mortreux, Eric Wattel
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Research Article Immunology

HTLV-1 propels untransformed CD4+ lymphocytes into the cell cycle while protecting CD8+ cells from death

Abstract

Human T cell leukemia virus type 1 (HTLV-1) infects both CD4+ and CD8+ lymphocytes, yet it induces adult T cell leukemia/lymphoma (ATLL) that is regularly of the CD4+ phenotype. Here we show that in vivo infected CD4+ and CD8+ T cells displayed similar patterns of clonal expansion in carriers without malignancy. Cloned infected cells from individuals without malignancy had a dramatic increase in spontaneous proliferation, which predominated in CD8+ lymphocytes and depended on the amount of tax mRNA. In fact, the clonal expansion of HTLV-1–positive CD8+ and CD4+ lymphocytes relied on 2 distinct mechanisms — infection prevented cell death in the former while recruiting the latter into the cell cycle. Cell cycling, but not apoptosis, depended on the level of viral-encoded tax expression. Infected tax-expressing CD4+ lymphocytes accumulated cellular defects characteristic of genetic instability. Therefore, HTLV-1 infection establishes a preleukemic phenotype that is restricted to CD4+ infected clones.

Authors

David Sibon, Anne-Sophie Gabet, Marc Zandecki, Christiane Pinatel, Julien Thête, Marie-Hélène Delfau-Larue, Samira Rabaaoui, Antoine Gessain, Olivier Gout, Steven Jacobson, Franck Mortreux, Eric Wattel

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Figure 3

Infected CD4+ lymphocytes that express tax display both nuclear abnormalities and cytokinesis defects.

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Infected CD4+ lymphocytes that express tax disp...
Clones 13 (A), 15 (C), 57 (B), 67 (F–H), and 68 (D and E) were cytospun, fixed, and stained with May-Grünwald and Giemsa. Label notation indicates the unique clone number, the phenotype, the infected or uninfected nature of the cells, and the corresponding amount of tax mRNA, measured in arbitrary units. Compared with uninfected CD8+ clones (A), HTLV-1–positive CD8+ clones (B) displayed enlarged cells with enlarged cytoplasm. Compared with uninfected CD4+ clones (C), HTLV-1–positive CD4+ clones (D and E) frequently display giant cells, some harboring enlarged nucleus (arrows). Multinucleated cells frequently displayed nuclei of heterogeneous sizes, as identified by arrowheads in E and G and shown at higher magnification in F. Chromatin bridges connecting nuclei in multinucleated cells are identified by smaller arrows in G and H. The distribution of cellular nuclearity according to phenotype and infectious status is shown in I. *P < 0.001; **P < 0.0001, infected vs. uninfected cells. Magnification, ×40 (A–E), ×100 –H).