Primary defect in CD8⁺ lymphocytes in the antibody deficiency disease (common variable immunodeficiency): abnormalities in intracellular production of interferon-gamma (IFN-γ) in CD28⁺ (‘cytotoxic’) and CD28⁻ (‘suppressor’) CD8⁺ subsets

We have measured by flow cytometry the ability of subsets of CD8⁺ CD3⁺ lymphocytes within mononuclear cell preparations to make intracellular cytokines (IL-2, tumour necrosis factor-alpha (TNF-α) and IFN-γ) on stimulation in vitro with phorbol myristate acetate (PMA) and ionomycin for 16 h. These CD8⁺ subsets were defined by the presence or absence of CD28 or HLA-DR. Subsets of normal CD8⁺ cells were compared with cells from the antibody deficiency disease common variable immunodeficiency (CVID). In CVID there was a significant increase in the production of IFN-γ in the CD8⁺ CD28⁺ subset (‘cytotoxic’). This reflects a shift in this disease towards an excessive Th1 response away from B cell help. Paradoxically, some CVID patients also showed a reduction in IFN-γ production in the CD8⁺ CD28⁻ subset (‘suppressor’) which was associated with a failure of these cells to maintain a state of activation after a stimulus in vitro. The B cell problem 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 CD28 subsets of CD8⁺ cells we have found in CVID may both be detrimental to a normal CD4-dependent immune response. The CD28⁻ suppressor subset expands and is unable to maintain activation and cytokine secretion, and the CD28⁺ cytotoxic subset is over-producing the Th1 cytokine IFN-γ.