Reduced interleukin-2 (IL-2) production in common variable immunodeficiency is due to a primary abnormality of CD4+ T cell differentiation.
Common variable immunodeficiency (CVI) is a condition characterized by hypogammaglobulinemia and impaired antibody responses, resulting in recurrent bacterial infections in untreated patients. In addition, affected individuals exhibit an increased incidence of autoimmunity, malignancy, and certain viral infections, suggesting the presence of an underlying generalized immune dysregulation. We have previously described a subgroup of CVI patients in whom T cells within PBMC populations exhibit a selective defect in lymphokine production. IL-2, IL-4, and IL-5 mRNA production was impaired in these patients, while proliferation, IL-2R expression, and c-myc mRNA production were normal. In the present series of experiments, using highly purified CD4+ T cells prepared by negative selection, we show that this lymphokine production defect is a primary abnormality of CVI CD4+ T cells: whereas CD4+ T cells from CVI patients proliferate normally in response to stimulation by PHA, staphylococcal enterotoxin B (SEB), or anti-CD2 antibodies, these stimuli induce significantly less IL-2 production than observed with CD4+ T cells from normal individuals. Furthermore, we show that this IL-2 production defect is not due to an accessory cell abnormality, since it was seen in the presence of normal (allogeneic) accessory cells, and patient accessory cells supported normal amounts of IL-2 production by PHA-stimulated CD4+ T cells obtained from normal individuals. Of interest, we also found that while IL-2 production by CD4+ T cells from CVI patients induced by stimulation with immobilized anti-CD3 antibody was reduced compared to CD4+ T cells from normal control individuals, this reduction was not statistically significant. Furthermore, stimulation of both CVI patient and normal CD4+ T cells with either ionomycin+phorbol myristate acetate or a combination of immobilized anti-CD3 antibody plus anti-CD28 antibody resulted in a 50-fold increase in IL-2 production compared to stimulation with immobilized anti-CD3 antibody alone, and, under these conditions, CVI and normal CD4+ T cells produced equivalent amounts of IL-2. Finally, minor defects in interferon-gamma production by CD4+ T cells from CVI donors were observed, but these were less severe than the IL-2 production defects and were not statistically significant. We conclude that a primary abnormality of lymphokine production exists in the CD4+ T cells of a subset of patients with CVI.(ABSTRACT TRUNCATED AT 400 WORDS)
Eisenstein
E M
EM
Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Jaffe
J S
JS
Strober
W
W
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D017074:Common Variable Immunodeficiency / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis*; D015759:Ionomycin / Q000276:immunology; D037102:Lectins; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets; D013755:Tetradecanoylphorbol Acetate
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D007376:Interleukin-2; D037102:Lectins; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate