THE BCL-6 PROTOONCOGENE CONTROLS GERMINAL-CENTER FORMATION AND TH2-TYPE INFLAMMATION

Structural alterations of the promoter region of the BCL-6 proto-oncog ene represent the most frequent genetic alteration associated with non -Hodgkin lymphoma, a malignancy often deriving from germinal-centre B cells. The BCL-6 gene encodes a zinc-finger transcriptional repressor normally expressed in both B cells and CD4(+) T cells within germinal centres, but its precise function is unknown. We show that mice defici ent in BCL-6 displayed normal B-cell, T-cell and lymphoid-organ develo pment but have a selective defect in T-cell-dependent antibody respons es. This defect included a complete lack of affinity maturation and wa s due to the inability of follicular B cells to proliferate and form g erminal centres. In addition, BCL-6-deficient mice developed an inflam matory response in multiple organs characterized by infiltrations of e osinophils and IgE-bearing B lymphocytes typical of a Th2-mediated hyp erimmune response. Thus, BCL-6 functions as a transcriptional switch t hat controls germinal centre formation and may also modulate specific T-cell-mediated responses. Altered expression of BCL-6 in lymphoma rep resents a deregulation of the pathway normally leading to B cell proli feration and germinal centre formation.