Defects in programmed call death (apoptosis) have been suggested as the cause of lymphoproliferation in T-LGL leukemia.

Normally, viral infection of a target cell leads to upregulation of the Fas antigen (receptor) on the cell surface, while antigen recognition of viral peptide causes upregulation of Fas ligand on cytotoxic T lymphocytes (CTL) (A). Binding of Fas ligand to Fas receptor results in death of the viral-infected target cell. The cytotoxic T lymphocyte then upregulates Fas antigen and is itself killed by the effects of Fas binding. Viral infection has been hypothesized as an initial stimulus for LGL leukemia (B). Since LGLs are cytotoxic T lymphocytes, they express both Fas antigen and Fas ligand. In this case, activation of the Fas antigen-Fas ligand pathway is defective. The LGLs do not undergo apoptosis. Instead, leukemic LGLs accumulate in the blood.