Figure 8.

Model indicating the two-step increase in ex vivo lymphocyte Fas surface expression. First, following human T-cell lymphotropic virus (HTLV)-1 infection, there is an increase in lymphocyte Fas expression (%) in AC. Second, upon progression to HAM/TSP, Fas expression is increased on a per-cell basis as mean fluorescence intensity (MFI) (Figures 2A,B). In agreement with its role as a death receptor, Fas⁺ cells in HC are primed to follow the apoptotic pathway, depicting nuclear condensation and cell blebbing, which is lost upon HTLV-1 infection (AC). In contrast, in HAM/TSP patients, Fas^hi cells are driven toward proliferation (Figures 6A,B). We recently discovered a genotype/phenotype interaction for the FAS -670 polymorphism with both apoptosis and proliferation in adult T-cell leukemia (ATL) patients and healthy controls (Khouri et al., submitted). This Fas^hi proliferating and chemotherapy-resistant leukemic phenotype is in agreement with the recently discovered CD4 T stem cell memory (Tscm) hierarchical apex of ATL. The same FAS -670 polymorphism also determined CD4 Tscm levels in a genome-wide twin study, confirming our hypothesis (Khouri et al., submitted). Therefore, a genetically determined interferon (IFN)/STAT1/FAS axis might help explain the proliferative, non-apoptotic phenotype in HAM/TSP suggesting CD4 Tscm as a pivotal factor not only in ATL but also in HAM/TSP pathogenesis. Considering STAT1 and FAS are in the HAM/TSP gene signature, our data further refine the data of Tattermusch et al. (7) It is not unexpected that a Tscm phenotype is absent from the disease signature, since Tscm are rare (2–3%) (45) and their genome-wide expression profile is intermediate between naïve and central memory T cells. However, Tscm cells have a Fas^hi, apoptosis-resistant, and drug-resistant, proliferative phenotype, in agreement with their stem cell-like nature. Interestingly, the proliferating cells in HAM/TSP patients were almost exclusively Fas^hi (Figure 6B), compatible with a Tscm phenotype.