Fas-FasL-mediated CD4+ T-cell apoptosis following stem cell transplantation

We report the preferential expression of Fas on CD4⁺ T cells and Fas ligand (FasL) on monocytes and their potential role in the selective loss of CD4⁺ T cells in breast cancer patients undergoing high-dose chemotherapy and peripheral blood stem cell transplantation (PSCT). A high frequency of apoptotic CD4⁺ T cells (28-51%) is observed during the first 100 days after PSCT concomitant with a significant increase in monocyte frequency and FasL expression (11.6-23%) on monocytes. The preferential expression of Fas on CD4⁺ T cells (73-92%) in the peripheral blood (PB) of these patients is associated with a significantly higher frequency of CD4⁺ T-cell apoptosis compared with CD8⁺ T cells (28-47%) and CD4⁺ T cells (46±5.7%) in normal PB. These data suggest that 'primed' Fas⁺ CD4⁺ lymphocytes interact with activated monocytes that express FasL, resulting in apoptosis, leading to deletion of CD4⁺ T cells, an inversion in the CD4:CD8 T-cell ratio, and immune dysfunction. The prevention of CD4⁺ T-cell apoptosis and improved immune reconstitution by the manipulation of PB stem cell products, blockade of Fas-FasL interactions, or cytokine support after transplantation may be important adjuvant immunotherapeutic strategies in patients undergoing high- dose chemotherapy and PSCT.