Suppression of autologous peripheral blood mononuclear cell proliferation by alveolar macrophages from young infants

Abstract

The lung is constantly exposed to respirable antigens and allergens. In the mature lung, alveolar macrophages (AM) prevent inappropriate immune activation by removing inhaled antigen via phagocytosis, and by directly suppressing pulmonary T cell proliferation [1]. Thus depletion of rat AM in vivo using cytotoxic liposomes removes the suppressive milieu, and results in an increase in the number of airway and parenchymal T lymphocytes, and an increased response to polyclonal and antigenic stimuli [2,3]. This innate lymphocytostatic activity of resident AM can be reproduced in vitro [4,5]. In both the rat and human, the pattern of suppression seen with AM in vitro is broadly similar. First, high AM : T cell ratios are suppressive, whereas low AM : T cell ratios are stimulatory [4]. Second, the concentration and nature of the stimulatory molecule determines the relative degree of suppression produced by AM; antigenic stimulation of T cell proliferation is more susceptible to AM suppression than mitogenic stimulation [6,7], and suppression is reduced when suboptimal doses of mitogen are used [8]. Third, AM are maximally suppressive if added at the onset of T cell proliferation, but are less so when added once T cell proliferation is established [8]. Fourth, suppression of T cell proliferation occurs partly by cell-to-cell contact and partly by soluble factors [6,9].There are, however, differences between animal models and humans. In rats and mice, the most important soluble factor mediating suppression by AM is nitric oxide (NO), which is released by interstitial macrophages [10] and AM, in response to cytokines released by T cells following cell-to-cell contact [9,11]. NO inhibits tyrosine phosphorylation of the kinases involved in production of the interleukin-2 (IL-2) receptor, the expression of which is essential for T cell proliferation [12]. Human AM also inhibit tyrosine phosphorylation of proteins involved in IL-2 receptor-associated signal transduction [6], but nitrogen intermediates are not involved [7]. In humans, cell-to-cell (AM/T cell) contact mechanisms may therefore play a more significant role. Indeed, the AM concentration required to induce suppression of T cell proliferation is orders of magnitude greater in humans [7], and the inhibitory effect of human AM can be reproduced partially using paraformaldehylde-fixed AM or a phospholipid component of the AM cell membrane [13]. SUMMARYMaintenance of lung homeostasis involves a complex interaction between T lymphocytes and alveolar macrophages (AM), in which AM suppress pulmonary T cell proliferation to antigenic stimuli. To assess whether AM-mediated suppression is attenuated in healthy young infants, AM and peripheral blood mononuclear cells (PBMC) were sampled prior to elective surgery. Children were divided into <4 months of age (Group I) and >4 months (Group II). Autologous PBMC and AM were co-cultured in vitro with phytohaemaglutinin (PHA) at AM : PBMC ratios ranging from 2 : 1 to 1 : 5. Methyl-tritiated thymidine was added after 48 h and uptake ...

Lower Expression of Inducible Nitric Oxide Synthase and Higher Expression of Arginase in Rat Alveolar Macrophages Are Linked to Their Susceptibility to Toxoplasma gondii Infection

“…In fact, alveolar macrophages play a compensating role in the regulation of the immune defense in mammals. The adaptive immunity is suppressed by alveolar macrophages to prevent nonselective destruction of normal pneumocytes by secreting Th2 cytokines, such as transforming growth factor-β (TGF- β ), interleukin-4 (IL-4), interleukin -10 (IL-10) and other small molecules [64]–[66]. Studies have shown that iNOS and arginase-1 are tightly regulated by Th1 cytokines (IFN-γ and TNF-α) and Th2 cytokines (IL-4 and IL-13) respectively [37], [67], [68].…”

TGF-β and CD23 are involved in nitric oxide production by pulmonary macrophages activated by β-glucan from Paracoccidioides brasiliensis

“…Lung infections, especially experimental paracoccidioidomycosis (PCMEx) [3][4][5], involve newly recruited CD11b + and CD23 + resident macrophages with potential immune disturbances for the host [6]. Several studies have implicated lung alveolar macrophages in the suppressive process of T-lymphocytes [7,8]. The mechanism by which pulmonary macrophages mediate the suppression of the T-lymphocytes proliferation in PCMEx is still unclear; however, it might involve soluble factors, either Th1/Th2 interleukins [9,10], CD23s [11], prostaglandins [12], regulatory T cells [13], antagonist of the IL receptors [14], accessory molecules, such as CD80 [15], CD86 [16], adhesion molecules [17][18][19][20] or genetic background of the host [21].…”

MARCO expression on pediatric alveolar macrophages

“…We have previously reported that in children undergoing elective surgery, AM are both morphologically and functionally immature (5, 6). A similar attenuation of MARCO expression in early childhood would have important consequences for vulnerability to both particulate air pollution and bacterial infection.…”