Immune mediated autologous cytotoxicity against hematopoietic precursor cells in patients with myelodysplastic syndrome

Abstract

An activated immune system has been observed in patients with myelodysplastic syndrome but its exact contribution to disease development and control is not fully clarified. On the one hand an activated and skewed T-cell repertoire has been reported, but on the other hand, decreased natural killer cell function has been found. Immune activation could reflect undesired autoimmune reactions against normal hematopoietic precursor cells as well as effective immune-surveillance against dysplastic clones. We have investigated immune effector cells (lymphocyte subsets, lymphocyte activation markers, and natural killer cells) of 40 low and intermediate risk myelodysplastic syndrome patients and compared them to those of 10 age-matched healthy donors. Furthermore, we have analyzed the cytotoxic capacity of effector cells against autologous bone marrow hematopoietic precursor cells of 8 myelodysplastic syndrome patients and 2 healthy donors. In myelodysplastic syndrome patients, we have found an activated state of lymphocytes, determined by increased percentages of effector T cells with cytotoxic profile, more skewing of the T-cell receptor Vbeta (TCR-Vbeta) repertoire, and decreased frequencies of regulatory T cells, when compared to healthy donors. The percentage of natural killer cells did not differ between myelodysplastic syndrome patients and healthy donors, but natural killer cells of myelodysplastic syndrome patients expressed increased levels of granzyme B. Finally, we have demonstrated non-MHC restricted autologous cytotoxicity up to 90% against aberrant hematopoietic precursor cells, presumably mediated by natural killer cells. Our data point to a role for active immune-surveillance in myelodysplastic syndrome, as demonstrated by activated T cells and TCR-Vss skewing. Autologous cytotoxicity against hematopoietic precursor cells was natural killer cell dependent, which points to an additional role for the innate immune system in immune-surveillance of myelodysplastic syndrome patients.