Immune reconstitution after bone marrow transplantation for combined immunodeficiencies: Down-modulation of Bcl-2 and high expression of CD95/Fas account for increased susceptibility to spontaneous and activation-induced lymphocyte cell death

We have studied the regeneration of T cell subsets and function after BMT in 21 children affected by combined immunodeficiency after BMT. In the first months, the striking predominance of CD4⁺ cells displayed the primed CD45R0⁺ phenotype and a high number of activated (HLA-DR⁺)T cells were observed.Regeneration of naive CD4⁺CD45RA⁺ cells correlated with the recovery of proliferative responses to mitogens (r = 0.64, P <0.001). Peripheral blood lymphocytes circulating after BMT undergo an increased process of in vitro cell death, resulting from two mechanisms: spontaneous apoptosis (SA), a consequence of defective production of IL-2 and down-regulation of Bcl-2 (P = 0.02 vs healthy controls), and high susceptibility to activation-induced cell death (AICD) after restimulation with mitogens. In accordance with the role of CD95/Fas in this latter process, we have observed a high level of CD95 expression (P <0.001 vs healthy controls), correlated with AICD (P <0.001) but not with SA, and decreasing with time after BMT (P <0.001). Both SA and AICD levels correlated with the presence of activated T cells and decreased with the progressive recovery of T cell proliferative response. Therefore, the lymphocyte hyperactivated status might explain their susceptibility to apoptosis and contribute to the genesis of immunodeficiency that follows BMT.