title: Interleukin-15 triggers activation and growth of the CD8 T-cell pool in extravascular tissues of patients with acquired immunodeficiency syndrome.
abstract: The impairment of interleukin-2 (IL-2) production occurs very early after human immunodeficiency virus (HIV) infection as a consequence of the quantitative depletion of Th1 cells. Despite the shift in cytokine production, most individuals develop an oligoclonal expansion of major histocompatibility complex restricted, HIV-specific CD8+ cytotoxic T lymphocytes (CTL) in different organs, suggesting that other cytokines replace IL-2 in initiating the tissue infiltration of CD8+ T cells. In this study we show that IL-15, a product of monocyte-macrophages and non-T cells and which has overlapping biological activities with IL-2, is involved in local cell networks accounting for the activation and expansion of CD8+ T-cell pools in a highly affected organ, ie, the lung. IL-15 induced proliferation of T cells obtained from the lower respiratory tract of HIV-infected patients with T-cell alveolitis and severe depletion of CD4+ T cells. Lung lymphocytes were CD45R0+/CD8+ T cells spontaneously expressing activation markers (CD69 and HLA-DR) and equipped with the receptorial subunits which bind IL-15, notably the beta and gamma chains of the IL-2 receptor (IL-2R) and the recently identified IL-15 binding-protein termed IL-15R alpha. Similar phenotypic findings were obtained after incubation of normal T cells with IL-15, which induced CD8+ T cells to express activation markers and to proliferate. The block of the IL-2R beta/IL-2R gamma complex with specific monoclonal antibodies abolished the T-cell stimulatory activity of IL-15 while the combination of IL-15 and tumor necrosis factor-alpha upregulated the proliferative response of lung T lymphocytes. The hypothesis that the tissue growth of lung CD8+ lymphocytes may involve cytokines produced from cells other than T lymphocytes was confirmed by the evidence that pulmonary macrophages expressed high levels of IL-15 and that anti-IL-15 antibodies inhibited the accessory function of alveolar macrophages on mitogen-induced CD8+ T-cell proliferation. Together, these results suggest that macrophage-derived cytokines produced at sites of T-cell infiltration play a role in the activation of HIV-specific CD8+ T-cell-mediated immune response.
authors.affiliation: Department of Clinical and Experimental Medicine, Padua University School of Medicine, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Agostini
authors.forename: L
authors.initials: L
authors.lastname: Trentin
authors.forename: R
authors.initials: R
authors.lastname: Sancetta
authors.forename: M
authors.initials: M
authors.lastname: Facco
authors.forename: C
authors.initials: C
authors.lastname: Tassinari
authors.forename: A
authors.initials: A
authors.lastname: Cerutti
authors.forename: M
authors.initials: M
authors.lastname: Bortolin
authors.forename: A
authors.initials: A
authors.lastname: Milani
authors.forename: M
authors.initials: M
authors.lastname: Siviero
authors.forename: R
authors.initials: R
authors.lastname: Zambello
authors.forename: G
authors.initials: G
authors.lastname: Semenzato
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000276:immunology / Q000473:pathology; D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000473:pathology; D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*; D007376:Interleukin-2 / Q000172:deficiency; D008168:Lung / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D011020:Pneumonia, Pneumocystis / Q000276:immunology / Q000473:pathology; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; C508024:IL15RA protein, human; D019409:Interleukin-15; D007376:Interleukin-2; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha