Enhanced apoptosis of T cells in common variable immunodeficiency (CVID): role of defective CD28 co-stimulation

CVID is a primary immune disorder in which hypogammaglobulinaemia may be as sociated with a number of T cell defects including lymphopenia, anergy, imp aired lymphocyte proliferation and deficient cytokine secretion. In this st udy we show that T cells of CVID subjects, in comparison with control T cel ls, undergo spontaneous apoptosis in culture and markedly accelerated apopt osis after gamma-irradiation. Although costimulation of the CD28 receptor f ollowing engagement of the TCR/CD3 receptor normally provides a second sign al necessary for IL-2 secretion, CD28 costimulation in CVID does not signif icantly increase IL-2 production, nor does this combination of activators e nhance the survival of irradiated CVID T cells, as it does for cultured nor mal T cells. Addition of IL-2 enhances CVID T cell survival, suggesting tha t the IL-2 signalling pathways are normal. CVID T cells have similar expres sion of Bcl-2 to control T cells. CD3 stimulation up-regulates T cell expre ssion of bcl-xL. mRNA for normal T cells, but anti-CD28 does not augment bc l-xL expression for CVID subjects with accelerated apoptosis. Defects of th e CD28 receptor pathway, leading to cytokine deprivation and dysregulation of bcl-xL, could lead to poor T cell viability and some of the cellular def ects observed in CVID.