PRIMARY DEFECT IN CD8(- ABNORMALITIES IN INTRACELLULAR PRODUCTION OF INTERFERON-GAMMA (IFN-GAMMA) IN CD28(+) (CYTOTOXIC) AND CD28(-) (SUPPRESSOR) CD8(+) SUBSETS() LYMPHOCYTES IN THE ANTIBODY DEFICIENCY DISEASE(COMMON VARIABLE IMMUNODEFICIENCY) )

We have measured by flow cytometry the ability of subsets of CD8(+)CD3 (+) lymphocytes within mononuclear cell preparations to make intracell ular cytokines (IL-2, tumour necrosis factor-alpha (TNF-alpha) and IFN -gamma) on stimulation in vitro with phorbol myristate acetate (PIMA) and ionomycin for 16h. These CD8(+) subsets were defined by the presen ce or absence of CD28 or HLA-DR. Subsets of normal CD8(+) cells were c ompared with cells from the antibody deficiency disease common variabl e immunodeficiency (CVID). In CVID there was a significant increase in the production of IFN-gamma in the CD8(+)CD28(+) subset ('cytotoxic') . This reflects a shift in this disease towards an excessive Th1 respo nse away from B cell help. Paradoxically, some CVID patients also show ed a reduction in IFN-gamma production in the CD8(+)CD28(-) subset ('s uppressor') which was associated with a failure of these cells to main tain a state of activation after a stimulus in vitro. The B cell probl em in this disease is known to be related to a failure of T cell help shown by an inability to produce the antigen-specific CD4(+) memory T cells needed for successful B cell maturation. The two pathological CD 28 subsets of CD8(+) cells we have found in CVID may both be detriment al to a normal CD4-dependent immune response. The CD28(-) suppressor s ubset expands and is unable to maintain activation and cytokine secret ion, and the CD28(+) cytotoxic subset is over-producing the Th1 cytoki ne IFN-gamma.