Cytotoxic Events Taking Place in the Lung of Patients with HIV-1 Infection: Evidence of an Intrinsic Defect of the Major Histocompatibility Complex-unrestricted Killing Partially Restored by the Incubation with rIL-2

Abstract

To characterize the cytotoxic events taking place in the lung of patients with HIV-1 infection, we studied the cells recovered from the bronchoalveolar lavage (BAL) of nine patients with AIDS, seven patients with AIDS-related complex, and two patients with lymphadenopathy. Phenotypic analysis was coupled to a series of functional evaluations of nonspecific cytotoxic abilities performed on lung effectors, including their property to bind K-562 targets, to release natural killer cytotoxic factor (NKCF), and to become cytotoxic following in vitro activation with rIL-2. Our results demonstrated that lung cells bearing the NK-related CD16, CD56, and CD57 antigens were quantitatively increased, irrespective of the disease stage. The majority of the cells also coexpressed the CD3 molecule and the alpha/beta T cell receptor (TCR), notably the phenotype characterizing MHC-unrestricted cytotoxic T cells. From a functional point of view, a severe impairment of the spontaneous cytotoxic ability was demonstrated in most patients. Evaluation at the single cell level showed a normal percentage of the effector/target conjugates formed by HIV-1 lymphocytes. The release of NKCF was undetectable in patients with AIDS even following lectin stimulation, whereas BAL cells from patients with earlier infection produced and/or could be triggered to release discrete amounts of NKCF by incubation with PHA. Studies designed to activate lung cytotoxic cells with rIL-2 showed that in most patients the stimulation of effector cells with rIL-2 enhanced the spontaneous killing and elicited a lymphokine-activated killer (LAK) phenomenon.(ABSTRACT TRUNCATED AT 250 WORDS)

High Proportion of Gamma-Delta T Cell Receptor Positive T Cells in Bronchoalveolar Lavage and Peripheral Blood of HIV-lnfected Patients with <i>Pneumocystis carinii</i> Pneumonias

“…Thus, T cell activa tion is a characteristic but general feature of pulmonary inflammation and can be detected not only in bronchial tissue and BAL, but also in peripheral blood. Our findings are also consistent with previously reported data showing a higher number of CD8/CD57 double-positive T cells in peripheral blood as well as in BAL of HIV-PCP individu als [10]. These cells, whose functions are not definitely es tablished, have been found to belong to the MHC-unrestricted cytotoxic system and display a dramatic decline in the ability of spontaneous killing during the course of the HIV infection.…”

“…Pneumocys tis carinii and other opportunistic microorganisms can be isolated from the respiratory tract of HIV-infected pa tients with an unusually high frequency [6], Hence, until now, little is known about the local immunological situa tion in the HIV-infected lung. A marked reduction of the pulmonary CD4/CD8 T cell ratio has been documented by several authors [7][8][9] along with a severe impairment of the spontaneous cytotoxic ability of lung T cells [10], Several recent studies have described a distinct subset of T lymphocytes that bear CD3 but lack CD4 and CDS [11,12], Most of these cells express a T cell antigen receptor (TCR) consisting of a y-and a 8-chain (TCR-y8-positivc T cells). TCR-y8-positivc T cells arc expressed early in on togeny in the fetal thymus before the appearance of TCR up + T cells, but constitute only a small proportion of adult thymocytes and peripheral blood lymphocytes in humans [13,14].…”

“…These cells, whose functions are not definitely es tablished, have been found to belong to the MHC-unrestricted cytotoxic system and display a dramatic decline in the ability of spontaneous killing during the course of the HIV infection. It has been shown in vitro that rIL-2 was able to restore the MHC-unrestricted cytotoxic ability of these pulmonary lymphocytes [10]. One can therefore hy pothesize that due to the marked reduction of activated CD4-positive T cells, IL-2 and other lymphokines are not sufficiently produced to functionally upregulate the MHC-unrestricted cytotoxic ability to normal levels.…”

Abnormalities in Host Defense Associated with HIV Infection

“…As with CD8+ T cells, NK cells may be impaired during HIV infection because they are dependent on signals from CD4+ T cells for optimal function 64 . Biological response modifiers such as recombinant IL-2 restore lytic ability in vitro 65 , and IFN–γ may augment NK cell activity in early stages of HIV infection 66 . The combination of IL-12 and IL-15 is effective in restoring expression of cytolytic molecules in NK cells from HIV-infected individuals 67 .…”

Involvement of natural killer cells in endogenous biological retranslation

“…Functionally active NK cells are also abtmdatll practically ill all peripheral compartnlents of the immune system. They realize particular functions in the lymphoid structures of the mucous membrancs of the bronchi [24], stomach [10], and intestine 147, 62], in the palatine tonsils [109], mesenteric lymph nodes [471, and skin (NK-like AsGMI § cells 1961), controlling the growth of trophoblast in the composition of the decidual membrane in vivo (CD56" large granular lymphocytes [13]). NK cells are the major producers of IFN in the body.…”