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

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Abstract
CVI is a primary immunodeficiency characterized by a failure of B cell differentiation 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 cytometry techniques and the expression of FasL mRNA using RT‐PCR in CVI T cells. We could not find any significant differences between CVI and normal subjects with regard to Fas expression, although there was a subgroup of CVI patients with very high Fas expression which was accompanied by an up‐regulation 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 as the bax/Bcl‐2 ratio, using flow cytometry techniques but could not detect any differences between CVI and normal subjects. Finally we analysed TNF‐RI and TNF‐RII mRNA expression in CD4+ and CD8+ CVI T cells using semiquantitative RT‐PCR and found a significant increase in expression of both TNF‐Rs in CD4+ T cells from CVI patients. Our data suggest that the increased expression of both TNF‐Rs on T cells may be one of the mechanisms responsible for the accelerated T cell apoptosis in CVI.

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