Immunological decoding of adult T cell leukemia – its cell of origin and oncogenesis

Abstract Adult T cell leukemia (ATL) is defined as a mature T cell neoplasm caused by human T cell leukemia virus type 1 (HTLV-1) and has been ascribed to the HTLV-1 gene products. However, the presence of asymptomatic carriers (ACs) accounting for the majority of HTLV-1 infected individuals who pass entire lives without developing ATL suggests that HTLV-1 infection alone is not sufficient for the onset of ATL. Studies with chronologically collected specimens from ATL patients or pre-onset individuals reported the presence of HTLV-1 infected CD4 + CD7 + CD45RA + T cells in blood in HTLV-1 ACs and the step wise development of malignant clones from CD7 + T cells, indicating that ATL is caused by accumulation of driver gene mutations as other cancers in general. Epidemiologically, mother-to-child infection of HTLV-1 during neonatal period is known to be the most important determinant of overall ATL incidence. This observation has attracted attention as getting to the core of the matter but has lacked hitherto any appropriate reasoning. Recent progress in basic immunology has disclosed that neonatal naïve T cells are, distinct from adult naïve T cells, exceptionally long-living and have propensity toward regulatory T cells. A minor population of stem cell like memory T cell (Tscm)-like HTLV-1 infected cells were detected in ATL patients and reported to repopulate ATL clones in immunodeficient mice. In this context, we need to trace the origin of ATL to HTLV-1 infected CD7 + T cells or Tscm in blood in ACs, and further to HTLV-1 infected neonatal naïve T cells. Latent infection of HTLV-1 has long-term effects on naïve T cells not only by viral gene products but also through their own pattern-recognition receptor-mediated reactions. In sum, the distinctive feature of ATL lies in its origin which may involve a neonatal naïve T cell and persistence of HTLV-1 provirus. The latter facilitates driver gene mutations when the infected cell increases frequency of cell division in the middle age of life.