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Functional characterization and modulation of cytokine production by CD8+ T
cells from human immunodeficiency virus-infected individuals
E Maggi, R Manetti, F Annunziato, L Cosmi, MG Giudizi, R Biagiotti, G Galli, G Zuccati and S Romagnani
Department of Clinical Immunology, Istituto di Medicina Interna e
Immunoallergologia, University of Florence, Firenze, Italy.
CD8+ T-cell clones were generated from peripheral blood mononuclear cells
(PBMC) of three human immunodeficiency virus (HIV)-seronegative individuals
and six HIV-seropositive individuals and assessed for their cytokine
secretion profile, cytolytic potential, and chemokine production. While the
great majority of CD8+ T-cell clones generated from HIV-seronegative
individuals produced interferon (IFN)-gamma, but not interleukin-4 (IL-4),
that is a type 1 cytotoxic (Tc1) profile, high numbers of CD8+ T-cell
clones generated from HIV-seropositive individuals produced IL-4 in
addition to IFN-gamma or IL-4 alone, thus showing a type 0 cytotoxic (Tc0)-
or a type 2 cytotoxic (Tc2) profile, respectively. Tc0/Tc2 cells displayed
lower cytolytic activity than Tc1 cells, including a reduced ability to
lyse autologous targets pulsed with HIV or HIV peptides. By contrast, the
production of chemokines RANTES and macrophage inflammatory protein-1alpha
was comparable in Tc1, Tc0, and Tc2 clones irrespective of whether they
were derived from HIV-seronegative or HIV-seropositive individuals. When
CD8+ T-cell clones were generated from PBMC cultures of HIV-seronegative
individuals conditioned with IL-4 plus an anti-IL-12 antibody (Ab), a shift
towards the Tc0/Tc2-like profile was observed. Conversely, the addition to
PBMC cultures of IL-12 plus an anti-IL-4 Ab shifted the differentiation of
CD8+ T cells from HIV-infected individuals towards the Tc1-like profile,
whereas IL-12 or anti-IL-4 Ab alone had a lower Tc1-promoting effect.
Irradiated PBMC from HIV-infected individuals, used as feeder cells,
shifted the differentiation of CD8+ T cells from a healthy HIV-seronegative
individual towards the Tc0/Tc2-like profile. On the other hand, a shift
towards the Tcl-like profile was noted in CD8+ T-cell clones generated from
the skin specimens of two HIV- seropositive patients with Kaposi's sarcoma,
successfully treated with IFN-alpha, in comparison to CD8+ clones generated
from the same skin areas before treatment. The IFN-alpha-induced Tc1 shift
could be prevented by the incubation of skin-infiltrating CD8+ T cells with
IL-4 before cloning. Taken together, these data indicate that both
defective production of IL-12 and abnormal IL-4 production in bulk PBMC
populations of HIV-infected individuals may contribute to the development
of high numbers of CD8+ T-cell clones showing a Tc0/Tc2- like phenotype and
reduced cytolytic potential against HIV itself. They also suggest that the
cytokine profile of CD8+ T-cell clones can be modulated by cytokines (or
anticytokine Ab) both in vitro and in vivo.
Volume 89,
Issue 10,
pp. 3672-3681,
05/15/1997
Copyright © 1997 by The American Society of Hematology
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