Functional characterization and modulation of cytokine production by CD8+ T cells from human immunodeficiency virus-infected individuals.
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.
Maggi
E
E
Department of Clinical Immunology, Istituto di Medicina Interna e Immunoallergologia, University of Florence, Firenze, Italy.
Manetti
R
R
Annunziato
F
F
Cosmi
L
L
Giudizi
M G
MG
Biagiotti
R
R
Galli
G
G
Zuccati
G
G
Romagnani
S
S
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D002999:Clone Cells / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D015658:HIV Infections / Q000276:immunology*; D018023:HIV Seronegativity / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000494:pharmacology; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000378:metabolism*; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000209:etiology / Q000276:immunology / Q000473:pathology; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000209:etiology / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D016898:Interferon-alpha; D008222:Lymphokines; D019402:Macrophage Inflammatory Proteins; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma