Functional abnormalities of CD8+ T cells define a unique subset of patients with common variable immunodeficiency.
A substantial subgroup of patients with common variable immunodeficiency (CVI) exhibit an abnormal T-cell phenotype characterized by a low CD4/CD8 ratio associated with a significant increase in the absolute number of CD8+ T cells (CVI4/8low patients). In the present study, we examined the phenotypic and functional properties of purified T-cell subsets in this group of CVI patients. CD8+ T cells from CVI4/8low patients manifested increased expression of HLA-DR and CD57 and decreased expression of CD45RA as compared with CD8+ T cells from normal controls. When stimulated with anti-CD3 and phorbol 12-myristate 13-acetate, purified patient CD8+ T cells exhibited significantly decreased proliferation, c-myc expression, and interleukin-2 (IL-2) production compared with that of normal CD8+ T cells. Nevertheless, mitogen-activated patient CD8+ T cells secreted elevated amounts of gamma-interferon and IL-5 and normal amounts of IL-4. This abnormal pattern of proliferation and cytokine production was limited to the CD8+ T-cell subset as CD4+ T cells from these patients exhibited normal proliferation and cytokine production. In further functional studies, purified CD8+ T cells from CVI4/8low patients manifested increased cytotoxic T-lymphocyte activity and suppressor activity, as compared with normal CD8+ T cells, when they were tested in (1) an anti-CD3 "redirected" cytotoxicity assay and (2) a suppressor assay consisting of CD8+ T cells and Staphylococcus aureus Cowan I (SAC) plus IL-2-stimulated normal (allogeneic) B cells. In the latter case, patient CD8+ T cells suppressed IgG production, but not IgM production. Finally, in studies to evaluate the role of patient CD8+ T cells in the pathogenesis of hypogammaglobulinemia, we determined the capacity of SAC and IL-2 to induce Ig production in highly purified patient B cells, ie, in the absence of patient CD8+ T cells. We found that, whereas B cells from one patient produced normal amounts of IgG, B cells from three patients were unable to produce normal amounts of IgG under these conditions. These data establish the phenotypic and functional characteristics of CD8+ T cells in CVI4/8low and clearly distinguish CVI4/8low patients from other patients with this syndrome. The data do not support the contention that hypogammaglobulinemia in CVI4/8low patients is due to a direct effect of CD8+ T cells on terminal B-cell differentiation, except in the occasional patient. The abnormal CD8+ T cells may, nevertheless, have more subtle effects of lymphoid function that play a role in disease pathogenesis.
Jaffe
J S
JS
Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
Strober
W
W
Sneller
M C
MC
D000917:Antibody Formation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016827:CD8 Antigens / Q000032:analysis*; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression; D016259:Genes, myc; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000276:immunology*; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000096:biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D016827:CD8 Antigens; D007376:Interleukin-2; D008222:Lymphokines; D012333:RNA, Messenger; D007371:Interferon-gamma