T cells from patients with common variable immunodeficiency undergo enhanced apoptosis and CD28 costimulation does not promote cell survival

The functional status of CD28 has been questioned in common variable immunodeficiency (CVI), since the CD28 knockout mouse, in analogy to CVI, has T cell proliferative defects, hypogammaglobulinemia and deficient IL2 production. As shown before, CVI T cell CD3/CD28-induced proliferation was similar to normals, but IL2 and IL10 production were 80% and 60% reduced respectively. Due to the fact that CD28 also promotes cell survival, probably by enhancing bcl-x expression, we studied the ability of CD3/CD28 costimulation to enhance cell survival of cultured or irradiated (Gy15) CVI T cells. First, as compared to normals, CVI T cells underwent increased spontaneous apoptosis in vitro (CVI dead cells vs normal ones: 7% vs 4% after 48 hrs, 12% vs 4% after 72 hrs, 17% vs 7% after 144 hrs). After gamma-irrradiation, the difference between CVI and normal cell death profile was even stronger (22% vs 11% 24 hrs after irradiation, 53% vs 32% 48 hrs after irradiation, 80% vs 68% 120 hrs after irradiation). As for normal cells, stimulation with anti-CD3 enhanced irradiated CVI T cell survival (70% more viability than non stimulated cells 48 hrs after irradiation), while the addition of CD28 significantly enhanced irradiated normal cell survival (17% more viability 120 hrs after irradiation) but it had no effect on CVI T cells. The relative deficiency of IL2 production could contribute to the lack of CD28 effect on cell viability since addition of Il2 clearly reduced apoptosis, but an additional functional impairment of the CD28 pathway is not excluded.