The circulating dendritic cell compartment in patients with chronic lymphocytic leukemia is severely defective and unable to stimulate an effective T-cell response.
Chronic lymphocytic leukemia (CLL), the most frequent leukemia in the Western world, is characterized by a profound dysregulation of the host immune system that has a marked impact on the clinical course of the disease. To date, the competence of the circulating dendritic cell (DC) compartment in CLL patients has not been investigated. To address this issue, we sorted DC precursors from the peripheral blood of CLL patients and found a profoundly altered compartment as compared with normal donors. CLL DCs proved a morphologically and phenotypically immature population, lacking the maturation antigen CD83 and the costimulatory molecule CD80, unable to induce a significant proliferative response in allo-mixed lymphocyte reaction, with a reduced ability to release interleukin 12 and to drive a type 1 T-cell response. To investigate whether these defects could be ascribed to inhibiting soluble factors released by the leukemic clone, DCs were generated in vitro from normal monocytes in the presence of allogeneic CLL cells. The addition of CLL cells induced similar markers of abnormal maturation and functional impairment with an inhibition in the expression of costimulatory molecules and a reduction of their allo-stimulatory ability. The blocking of interleukin 6 activity was able to revert the inhibition in a proportion of patients. Taken together, these findings indicate that mechanisms of tumor-induced DC inhibition are operational in CLL patients, resulting in both maturative and functional defects in the circulating DC compartment, with a potential functional impact in the regulation of in vivo T-cell immune responses.
Orsini
Enrica
E
Dipartimento di Biotecnologie Cellulari ed Ematologia, University La Sapienza, Via Benevento 6, 00161 Rome, Italy. orsini@bce.uniroma1.it
Guarini
Anna
A
Chiaretti
Sabina
S
Mauro
Francesca Romana
FR
Foa
Robert
R
D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*