Human alveolar macrophages present antigen ineffectively due to defective expression of B7 costimulatory cell surface molecules.

Chelen, C. J.; Fang, Yu; Freeman, G J; Secrist, Heather; Marshall, Jason D.; Hwang, P. T.; Frankel, Lorry R.; DeKruyff, Rosemarie H.; Umetsu, Dale T.

doi:10.1172/jci117796

Cited by 156 publications

(103 citation statements)

References 42 publications

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“…Previous studies have suggested that alveolar macrophages are poor APCs, at least in part because they express little or no B7 costimulatory molecules (14,26). IL-10 is known to suppress LPSinduced B7 expression and cytokine synthesis by peripheral blood monocytes in vitro (16,27).…”

Section: Discussionmentioning

confidence: 99%

“…We used anti-CD3 as a mitogen because this stimulus had previously been shown to require costimulation via B7 (14). First, we compared the ability of BALMs with that of adherence purified splenic macrophages to provide costimulation with anti-CD3 Ab, using purified splenic T cells as the responders.…”

Section: Costimulatory Effect Of Balms For T Cellsmentioning

confidence: 99%

“…Others have previously shown that normal BALMs have poor costimulatory activity in T cell proliferation assays and that they fail to express the T cell costimulatory molecules B7-1 and B7-2 (CD80 and CD86, respectively) (14). It has also been shown that IL-10 down-regulates the expression of MHC class II (MHC-II) (15) and inhibits expression of B7 molecules by blood monocytes in response to LPS stimulation in vitro (16).…”

mentioning

confidence: 99%

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Functional IL-10 Deficiency in the Lung of Cystic Fibrosis (cftr−/−) and IL-10 Knockout Mice Causes Increased Expression and Function of B7 Costimulatory Molecules on Alveolar Macrophages

Šoltýs

Bonfield

Chmiel

et al. 2002

The Journal of Immunology

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Alveolar macrophages are poor APCs that only minimally express B7 costimulatory molecules. Because our previous data suggest that bronchial epithelial cells constitutively secrete IL-10, and IL-10 inhibits B7 expression in vitro, we hypothesized that this IL-10 is responsible for suppressing B7 expression on macrophages that enter the airways. Furthermore, because we have shown that cystic fibrosis (CF) lungs are deficient in IL-10, we hypothesized that bronchoalveolar macrophages (BALMs) from cystic fibrosis transmembrane conductance regulator (CFTR)−/− as well as IL-10−/− mice might express increased B7. Immunofluorescence for B7 was positive on BALMs from CF patients and CFTR−/− and IL-10−/− mice, but was negative on controls. FACS showed that 63.9% of BALMs from IL-10−/− mice were B7-1 positive, as were 67.4% of BALMs from CFTR−/− mice, whereas <7% of BALMs from wild-type controls were positive. Using BALMs to costimulate splenic T cells with anti-CD3 as a mitogen showed 9202 ± 2107 cpm [3H]thymidine incorporation for BALMs from IL-10−/− mice and 4082 ± 1036 cpm for BALMs from CFTR−/− mice, but <200 cpm with BALMs from either type of +/+ mouse. Treatment of CFTR−/− mice with recombinant mouse IL-10 reduced the B7 expression and costimulatory activity of the BALMs. These data suggest that the IL-10 secreted in the healthy lung may be responsible for the absence of B7 and poor costimulatory activity of BALMs and that reductions of pulmonary IL-10 in CF may enhance B7 expression and local immune responses.

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Section: Discussionmentioning

confidence: 99%

Section: Costimulatory Effect Of Balms For T Cellsmentioning

confidence: 99%

mentioning

confidence: 99%

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Functional IL-10 Deficiency in the Lung of Cystic Fibrosis (cftr−/−) and IL-10 Knockout Mice Causes Increased Expression and Function of B7 Costimulatory Molecules on Alveolar Macrophages

Šoltýs

Bonfield

Chmiel

et al. 2002

The Journal of Immunology

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“…In two studies using AM isolated by BAL and evaluated by flow cytometry, normal AM were reported to be B7-1 ¹ and weakly positive for B7-2, and the expression of these costimulatory molecules was not increased by culture in the presence of IFN-g [14,15]. From these results, the authors suggested that the poor ability of AM to serve as accessory cells for antigen-induced T cell proliferation is due to defective expression of B7 molecules.…”

Section: Discussionmentioning

confidence: 99%

In situexpression of B7 and CD40 costimulatory molecules by normal human lung macrophages and epithelioid cells in tuberculoid granulomas

Stolzmann

Boussaud

Moreau

et al. 1999

Clinical and Experimental Immunology

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SUMMARYNormal alveolar macrophages (AM) are not efficient in inducing the proliferation of resting T lymphocytes, and, rather, tend to inhibit pulmonary immune responses. In contrast, epithelioid cells (EC), activated macrophages that play an essential role in the course of granulomatous responses, appear to stimulate T cell proliferation efficiently. The inability of macrophages to deliver potent costimulatory signals through the B7/CD28 and CD40/CD40L pathways could explain their weak accessory cell activity. Using MoAbs and immunohistochemical techniques, however, we found that essentially all AM in normal human lung tissue expressed B7-1, B7-2 and CD40 molecules, and most of these cells were strongly positive. Pulmonary macrophages in other compartments also expressed these costimulatory molecules; no differences in expression were observed comparing macrophages from smokers and non-smokers. Most AM recovered by bronchoalveolar lavage from normal lung segments also strongly expressed B7-1, B7-2 and CD40 molecules. In comparison, resting blood monocytes were B7-1 ¹ and only moderately positive for B7-2. Activation of monocytes with lipopolysaccharide (LPS) induced expression of these costimulatory molecules to levels similar to that of AM from the control subjects. EC in granulomatous lesions also expressed easily detectable levels of B7-1, B7-2 and CD40. T lymphocytes within and surrounding the granulomas expressed CD28, the counter-receptor for B7, and many of these T cells also expressed B7-1 and B7-2. These findings suggest that both AM and EC can deliver costimulatory signals through B7-1, B7-2 and CD40 molecules, and indicate that the impairment in accessory cell activity observed for normal AM cannot be attributed to the absence of expression of these costimulatory molecules.

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“…Hence, activation of DC is continuously attenuated by immunosuppressive cytokines 3 such as transforming growth factorb (TGFb). [4][5][6] TGFb belongs to a well-defined multi-potent cytokine family involved in many pathophysiological events. 7 Three isoforms (TGFb1, TGFb2 and TGFb3) that bear overlapping activities are expressed in mammals.…”

Section: Introductionmentioning

confidence: 99%

TGFβ-dependent gene expression profile during maturation of dendritic cells

et al. 2007

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Primary immune response to pathogens involves the maturation of antigen-presenting dendritic cells (DC). Bacterial lipopolysacharride (LPS) is a potent inducer of DC maturation, whereas the transforming growth factor b (TGFb) attenuates much of this process. Here, we analyzed the global gene expression pattern in LPS-treated bone marrow derived DC during inhibition of their maturation process by TGFb. Exposure of DC to LPS induces a pronounced cell response, manifested in altered expression of a large number of genes. Interestingly, TGFb did not affect most of the LPS responding genes. Nevertheless, analysis identified a subset of genes that did respond to TGFb, among them the two inflammatory cytokines interleukin (IL)-12 and IL-18. Expression of IL-12, the major proinflammatory cytokine secreted by mature DC, was downregulated by TGFb, whereas the expression level of the proinflammatory cytokine IL-18, known to potentiate the IL-12 effect, was upregulated. Expression of the peroxisome proliferator-activated receptor g (PPARg) increased in response to TGFb, concomitantly with reduced expression of chemokine receptor 7 (CCR7). This finding supports the possibility that TGFbdependent inhibition of CCR7 expression in DC is mediated by PPARg.

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Human alveolar macrophages present antigen ineffectively due to defective expression of B7 costimulatory cell surface molecules.

Cited by 156 publications

References 42 publications

Functional IL-10 Deficiency in the Lung of Cystic Fibrosis (cftr−/−) and IL-10 Knockout Mice Causes Increased Expression and Function of B7 Costimulatory Molecules on Alveolar Macrophages

Functional IL-10 Deficiency in the Lung of Cystic Fibrosis (cftr−/−) and IL-10 Knockout Mice Causes Increased Expression and Function of B7 Costimulatory Molecules on Alveolar Macrophages

In situexpression of B7 and CD40 costimulatory molecules by normal human lung macrophages and epithelioid cells in tuberculoid granulomas

TGFβ-dependent gene expression profile during maturation of dendritic cells

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