CD8 T-cell infiltration in extravascular tissues of patients with human immunodeficiency virus infection. Interleukin-15 upmodulates costimulatory pathways involved in the antigen-presenting cells T-cell interaction

Interleukin (IL)-15 regulates the proliferative activity of the CD8(+) T-ce ll pool in human immunodeficiency virus (HIV)-infected patients, thereby co ntributing to the maintenance of the CD8+ T-cell-mediated immune response a gainst HIV In extravascular tissues, including the lung. However, the effec ts of IL-15 on antigen-presenting cells (APC) during HIV infection are stil l unclear. In this study, we evaluated whether IL-15 regulates the macropha ge stimulatory pathways governing inflammatory events that take place in th e lung of patients with HIV infection. As a first step we evaluated the in vitro effects of IL-15 on lung macrophages retrieved from the respiratory t ract of eight normal subjects. Although macrophages from uninfected individ uals expressed the IL-15 binding proteins (IL-15R alpha and the common gamm a c) at resting conditions, they did not express IL-15 messenger RNA (mRNA) . However, a 24-hour stimulation with IL-15 induced the expression of inter feron-gamma (IFN-gamma) and IL-15 itself, suggesting a role for this cytoki ne in the activation of the pulmonary macrophage pool during inflammation. As a confirmation of the role of IL-15 in this setting, at resting conditio ns, alveolar macrophages of patients with HIV infection and T-cell alveolit is expressed IL-15, IFN-gamma, and IL-15 binding proteins; showed an upmodu lation of costimulatory molecules, B7 and CD72, which are involved in the A PC of macrophages; and behaved as effective accessory cells because they el icited a strong proliferation of T cells. The accessory effect was inhibite d by pretreatment with anti-CD72, anti-B7 (CD80 and CD86), end anti-IL-15 m onoclonal antibodies (MoAb). We then investigated the relationship between IL-15 and the expression of costimulatory molecules by macrophages. A 24-ho ur stimulation of IL-15R alpha(+)/gamma c(+) macrophages with IL-15 upregul ated the expression of CD80 and CD86. The evidence that IL-15 upregulates t he expression of coligands that favor the contact between T cells and APC, per se, triggers T-cell activation and proliferation and acts as a chemoatt ractant for T cells, suggests that IL-15 plays a key role in Tc1-mediated d efense mechanisms taking place in extravascular tissues of patients with HI V disease. (C) 1999 by The American Society of Hematology.