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

Abstract

Summary: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 Ͻ 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 Ͻ 0.001 vs healthy controls), correlated with AICD (P Ͻ 0.001) but not with SA, and decreasing with time after BMT (P Ͻ 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. Keywords: bone marrow transplant; severe combined immunodeficiency; Fas; Bcl-2; apoptosis The majority of primary immunodeficiency disorders results from abnormalities in the differentiation or function of immunocompetent cells originating from haemopoietic stem cells. Stem cell transplantation, generally performed with BMT, therefore offers a therapeutic approach in these patients.1,2 Recovery of the T cell number after BMT is slow. The recovery of T cell function is even slower, causCorrespondence: Dr P Airò,

Erratum for vol. 95, p. 3635

“…21,22 This is suggested by studies in patients with TCD due to HIV infection showing increased susceptibility of T cells to apoptosis with restimulation in vitro [23][24][25][26][27] and by direct labeling studies in vivo. [28][29][30] Although these observations could potentially relate to direct or indirect effects of HIV, similar results have been observed in T-cell-depleted hosts after intensive chemotherapeutic regimens 20 and after stem cell transplantation, 31 suggesting that increased susceptibility to cell death is a common phenomenon in regenerating T-cell populations. Thus, a propensity for programmed cell death in peripherally expanding T-cell populations may also limit the capacity of peripheral expansion to restore host immune competence.…”

“…Although the finding of increased annexin V staining of restimulated, peripherally expanding T cells, along with the findings of other investigators, 20,31 suggests that these cells are prone to apoptosis, it is unclear whether this process contributes to the limitation in immune responses observed in hosts reconstituted in this manner. If the loss of peripherally expanding T cells to apoptosis in our skin graft rejection model contributes to the inability to induce responses to HY antigen in animals reconstituted from a suboptimal T-cell number, we hypothesized that inhibition of apoptosis in vivo could restore HY-mediated graft rejection.…”

“…Based on observations made in clinical settings associated with TCD, 20,31 we hypothesized that increased apoptosis (A) Adult thymectomized, C57BL/6 females were T cell depleted and grafted with male tail skin as described in "Materials and methods." Primed cells were collected from the draining LN of T-cell-replete syngeneic female mice 3 weeks after successful male skin graft rejection, teased into a single-cell suspension, and injected via the tail vein 24 hours after skin grafting.…”

Classical Ataxia Telangiectasia Patients Have a Congenitally Aged Immune System with High Expression of CD95

“…Peripheral T cell depletion associated with increased serum IL-7 concentration and consequent CD95 upregulation in lymphopenic individuals has been reported in HIV patients (12) and bone marrow transplant recipients (13). Significantly higher CD95 expression on A-T patient T cells compared with controls has also been described, although IL-7 was not investigated (5,7).…”

“…Alternatively, increased availability of IL-7 as a response to T cell lymphopenia may also contribute to the lymphopenia by upregulating CD95 on T cells and consequently increasing their sensitivity to CD95-mediated apoptosis (12,13). Peripheral T cell depletion associated with increased serum IL-7 concentration and consequent CD95 upregulation in lymphopenic individuals has been reported in HIV patients (12) and bone marrow transplant recipients (13).…”