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 associated with a number of T cell defects including lymphopenia, anergy, impaired lymphocyte proliferation and deficient cytokine secretion. In this study we show that T cells of CVID subjects, in comparison with control T cells, undergo spontaneous apoptosis in culture and markedly accelerated apoptosis after gamma-irradiation. Although costimulation of the CD28 receptor following engagement of the TCR/CD3 receptor normally provides a second signal necessary for IL-2 secretion, CD28 costimulation in CVID does not significantly increase IL-2 production, nor does this combination of activators enhance the survival of irradiated CVID T cells, as it does for cultured normal T cells. Addition of IL-2 enhances CVID T cell survival, suggesting that the IL-2 signalling pathways are normal. CVID T cells have similar expression of Bcl-2 to control T cells. CD3 stimulation up-regulates T cell expression of bcl-xL mRNA for normal T cells, but anti-CD28 does not augment bcl-xL expression for CVID subjects with accelerated apoptosis. Defects of the CD28 receptor pathway, leading to cytokine deprivation and dysregulation of bcl-xL, could lead to poor T cell viability and some of the cellular defects observed in CVID.
Di Renzo
M
M
Division of Clinical Immunology, The Mount Sinai Medical Center, New York City, NY, USA. cd28apo@hotmail.com
Zhou
Z
Z
George
I
I
Becker
K
K
Cunningham-Rundles
C
C
D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D018106:CD28 Antigens / Q000378:metabolism*; D017252:CD3 Complex / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D002648:Child; D017074:Common Variable Immunodeficiency / Q000276:immunology*; D004261:DNA Replication; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000502:physiology*; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D018106:CD28 Antigens; D017252:CD3 Complex; D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein