The life cycle of cutaneous T cell lymphoma reveals opportunities for targeted drug therapy

The diverse clinical presentations of cutaneous T cell lymphoma (CTCL) have been unified by immunologic characterization of the malignant T cells as an expansion of clonal, CD4+ inducer T cells with affinity for epidermal association with Langerhans cells (LC), an immature member of the dendritic cell (DC) family. Features of the life cycle of CTCL have recently been elucidated through development of an in vitro cell culture system. In this system, the proliferation and survival of the CTCL cells is tied to an association with immature monocyte-derived DC. Growth of the CTCL cells requires direct contact with the DC and both cell types survive in the presence of supportive cytokines for 3 months. Separation of the CTCL cells and the DC, or DC maturation truncates the synergy between the two cell populations and results in rapid death of both cell types. The CTCL cells perpetuate DC immaturity and survival through secretion of interleukin 10 (IL10) and transforming growth factor-beta (TGF-beta). The immature DC are aggressively phagocytic and can engulf apoptotic CTCL cells that have exhausted their proliferative potential and present peptides derived from the apoptotic material in class II MHC molecules to the T cell receptor (TCR) of the CD4+ CTCL cell. CTCL cells are induced to become T-regulatory (Treg) cells when their TCR is triggered by DC class II presentation of peptides derived from apoptotic material. Treg CTCL cells suppress immune responses and secrete IL10 and TGF-beta, cytokines that perpetuate DC immaturity, providing continued opportunity for DC stimulation of CTCL cell growth. Understanding the CTCL cell life cycle unveils a variety of potential targets that can be exploited for therapeutic intervention.