Enhanced T cell apoptosis in common variable immunodeficiency: negative role of the fas/fasligand system and of the Bcl-2 family proteins and possible role of TNF-RS

CVI is a primary immunodeficiency characterized by a failure of B cell diff erentiation associated with an array of T cell defects, such as enhanced T cell apoptosis. In this study we investigated the mechanisms underlying CVI enhanced T cell death. We analysed both the expression of Fas using flow c ytometry techniques and the expression of FasL mRNA using RT-PCR in CVI T c ells. We could not find any significant differences between CVI and normal subjects with regard to Fas expression, although there was a subgroup of CV I patients with very high Fas expression which was accompanied by an up-reg ulation of FasL mRNA. However, attemps to induce Fas-mediated apoptosis in these high Fas expressing cells, as evaluated by propidium iodide staining and APO2.7 staining, were unsuccessful. We also investigated intracellular levels of Bcl-2, bcl-xl and bax in CD4(+) and CD8(+) CVI T cells, as well a s the bax/Bcl-2 ratio, using flow cytometry techniques but could not detect any differences between CVI and normal subjects. Finally we analysed TNF-R I and TNF-RII mRNA expression in CD4(+) and CD8(+) CVI T cells using semiqu antitative RT-PCR and found a significant increase in expression of both TN F-Rs in CD4(+) T cells from CVI patients. Our data suggest that the increas ed expression of both TNF-Rs on T cells may be one of the mechanisms respon sible for the accelerated T cell apoptosis in CVI.