DEFECTIVE INTEGRATION OF ACTIVATING SIGNALS DERIVED FROM THE T-CELL RECEPTOR (TCR) AND COSTIMULATORY MOLECULES IN BOTH CD4(-LYMPHOCYTES OF COMMON VARIABLE IMMUNODEFICIENCY (CVID) PATIENTS() AND CD8(+) T)

CVID is characterized by hypogammaglobulinaemia and impaired antibody production. Previous studies demonstrated defects at the T cell level. In the present study the response of purified CD4(+) and CD8(+) T lym phocytes to stimulation with anti-TCR monoclonal antibody (the first s ignal) in combination with anti-CD4 or anti-CD8, anti-CD2 and anti-CD2 8 MoAbs (the costimulatory signals) was investigated. Both CD4(+) and CD8(+)T cells from the patients showed significantly reduced IL-2 rele ase following stimulation via TCR and costimulation via CD4 or CD8 and CD2, respectively. However, normal IL-2 production following TCR plus phorbol myristate acetate (PMA) costimulation and normal expression o f an early activation marker, CD69, after TCR + CD28 stimulation indic ated that TCR was able to transduce a signal. Furthermore, both IL-2 a nd IL-4 release were impaired in CD4(+) lymphocytes following TCR+CD28 stimulation. In addition,stimulation via TCR+CD28 resulted in signifi cantly decreased expression of CD40 Ligand in the patients. These resu lts suggest that the integration of activating signals derived from th e TCR and costimulatory molecules is defective in CVID patients; the d efect is not confined to costimulation via a single molecule, or restr icted to cells producing Th1-type cytokines such as IL-2, and is expre ssed in both CD4(+) and CD8(+) T cell subsets.