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Functional abnormalities of CD8+ T cells define a unique subset of patients
with common variable immunodeficiency
JS Jaffe, W Strober and MC Sneller
Mucosal Immunity Section, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, MD.
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.
Volume 82,
Issue 1,
pp. 192-201,
07/01/1993
Copyright © 1993 by The American Society of Hematology
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