Role for p53 in activation-induced cell death of T cell-independent B cell clones (104.16)

Abstract

Abstract B cell immunity involves clonal proliferation, differentiation of selected progeny into memory/effector cells, and activation-induced cell death (AICD) of others. Clonal expansion and contraction occur in human B2 cell cultures activated by surrogate C3dg-Ag and IL-4 ± BAFF (J Immunol 175:6143). The mechanism was here studied. Pro- and anti-apoptotic proteins were assessed by immunoblotting prior(d3-4) or during (d5-6) AICD and by immunostaining CFSE-labeled cells. Evidence of lesser Bim but elevated p53 and downstream proteins suggested p53-mediated apoptosis, perhaps triggered by expressed activation-induced cytosine deaminase (AID) (J Immunol 185:5300). This was reinforced by findings that AICD is reduced (but not ablated) by p53 siRNA or genetic deficiency in p53 or AID, in similarly activated mouse cells. A significant drop in Bcl-2 in dividing blasts preceded AICD and its importance was substantiated by greater clonal burst size in Bcl-2 TG-cultures. In germinal centers (GC), p53 is repressed by Bcl-6, resulting in infrequent p53 mutations in GC lymphomas (Phan et al., Nature 432:635). Our study suggests that B cell tumors with a higher incidence of p53 mutations may arise from inflamed peripheral tissues. In the latter, recirculating B cells will encounter C3dg-coated microbes or apoptotic cells and IL-4 and BAFF from innate immune system cells. The latter milieu would foster T cell-independent B cell growth and encourage positive selection of p53 mutants.