Evaluación de la respuesta migratoria de los linfocitos T de pacientes con leucemia linfocítica crónica de células B (LLC) inducida por las quimiocinas CXCL12, CCL19 y CCL21: su asociación con los factores de mal pronóstico ZAP-70 y CD38.

BORGE MERCEDES; NANNINI PAULA ROMINA; MORANDE PABLO; ZANETTI SAMANTA; GALLETTI JEREMÍAS; BEZARES FERNANDO; AVALOS SANCHEZ JULIO; GIORDANO MIRTA; GAMBERALE ROMINA

Mar del Plata, Buenos Aires. Argentina.

Congreso; LIV Reunión Científica de la Sociedad Argentina de Investigación Clínica – LVII Reunión Científica de la Sociedad Argentina de Inmunología.; 2009

Leukemic B cells from CLL patients proliferate within lymph nodes and bone marrow in particular areas termed proliferation centers in close contact with T cells and CXCL12-, CCL21- and CCL19-producing stromal cells. CLL patients with poor prognosis, who develop an aggressive disease and die few years after diagnosis, usually express the prognostic markers ZAP-70 and CD38 in their leukemic cells. By contrast, the absence of these molecules is mostly found in leukemic cells from good prognosis patients, who exhibit a more indolent disease. We have previously shown that T cells from CLL ZAP-70- patients have a lower migratory capacity towards CXCL12 than T cells from ZAP-70+ patients. The aims of this study were: a) to compare the migratory potential of T cells from CLL patients and healthy donors towards CXCL12, CCL21 and CCL19 and b) to study the underlying mechanism involved in the different migratory capacity towards CXCL12 of T cells from ZAP-70+ and ZAP-70- patients. We performed chemotaxis assays with T cells from CLL patients (n=31) and healthy donors (n=22) and found that T cells from CLL patients have a lower migratory response towards the three chemokines (p<0,001) despite similar chemokine receptor expression. We observed a similar migratory capacity towards CCL21 and CCL19 between CLL patients segregated by ZAP-70 or CD38. In addition we found that the lower migratory response of T cells from ZAP-70- patients towards CXCL12 (p=0,002) seems to depend on signals provided by the leukemic cells (n=10, p=0,002). Moreover, the lower migratory response was not associated to differences in CXCR4 internalization, actin polymerization or to a lower expression of CXCR4, CD45, CD38 or ZAP-70 on T cells from ZAP-70- patients. The impaired migratory response of T cells form CLL patients towards CCL21 and CCL19 might favor the defective immune response observed in these patients. On the other hand, the lower migratory response of T cells from ZAP-70- patients to CXCL12 could impair the access of T cells to proliferation centers. Since T lymphocytes help CLL cells to survive and proliferate, the low migratory response towards CXCL12 in T cells from ZAP-70- CLL patients might favor the indolent clinical course of the diseases in these patients.