Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Sep 19;84(10):2914-21.
doi: 10.1128/IAI.00533-16. Print 2016 Oct.

Neonatal Fc Receptor Regulation of Lung Immunoglobulin and CD103+ Dendritic Cells Confers Transient Susceptibility to Tuberculosis

Alexis Vogelzang  1 , Laura Lozza  2 , Stephen T Reece  2 , Carolina Perdomo  2 , Ulrike Zedler  2 , Karin Hahnke  2 , Dagmar Oberbeck-Mueller  2 , Anca Dorhoi  2 , Stefan H E Kaufmann  1
Affiliations

Neonatal Fc Receptor Regulation of Lung Immunoglobulin and CD103+ Dendritic Cells Confers Transient Susceptibility to Tuberculosis

Alexis Vogelzang et al. Infect Immun. .

Abstract

The neonatal Fc receptor (FcRn) extends the systemic half-life of IgG antibodies by chaperoning bound Fc away from lysosomal degradation inside stromal and hematopoietic cells. FcRn also transports IgG across mucosal barriers into the lumen, and yet little is known about how FcRn modulates immunity in the lung during homeostasis or infection. We infected wild-type (WT) and FcRn-deficient (fcgrt(-/-)) mice with Pseudomonas aeruginosa or Mycobacterium tuberculosis to investigate whether recycling and transport of IgG via FcRn influences innate and adaptive immunity in the lung in response to bacterial infection. We found that FcRn expression maintains homeostatic IgG levels in lung and leads to preferential secretion of low-affinity IgG ligands into the lumen. Fcgrt(-/-) animals exhibited no evidence of developmental impairment of innate immunity in the lung and were able to efficiently recruit neutrophils in a model of acute bacterial pneumonia. Although local humoral immunity in lung increased independently of the presence of FcRn during tuberculosis, there was nonetheless a strong impact of FcRn deficiency on local adaptive immunity. We show that the quantity and quality of IgG in airways, as well as the abundance of dendritic cells in the lung, are maintained by FcRn. FcRn ablation transiently enhanced local T cell immunity and neutrophil recruitment during tuberculosis, leading to a lower bacterial burden in lung. This novel understanding of tissue-specific modulation of mucosal IgG isotypes in the lung by FcRn sheds light on the role of mucosal IgG in immune responses in the lung during homeostasis and bacterial disease.

PubMed Disclaimer

Figures

FIG 1
FIG 1
FcRn influences local immunoglobulin (Ig) homeostasis in lung, modulating resident CD103+ DC. (A) Relative levels of Ig isotypes in serum, homogenized lung tissue (Parenchyma), and bronchoalveolar lavage fluid (Lavage) measured by Bioplex. Box and whisker plots show the mean and total and interquartile ranges of cumulative data from 2 experiments where n = 10. Asterisks indicate P values (*, P < 0.05; **, P < 0.01; ***, P < 0.001). (B) Total numbers of innate and lymphoid immune cells analyzed by flow cytometry in lung. Data points show cumulative data from 3 experiments with the median and interquartile range. Alv Mac, alveolar macrophage; Mac/mono, macrophage/monocyte. (C) Representative flow cytometry data from the 2 experiments (n = 5), showing Ly6G-B220-CD11c+ MHCII+ DC from naive lung, as well as a histogram of XCR1 expression on overlaid WT and fcgrt−/− CD103+ DC populations.
FIG 2
FIG 2
FcRn is not required for recruitment of neutrophils or bactericidal activity in P. aeruginosa infection. WT and fcgrt−/− mice were vaccinated intranasally 3 times with paraformaldehyde-fixed P. aeruginosa. At 40 days postvaccination, vaccinated mice (i.n vac) and sham controls (PBS) were intratracheally infected with 4 × 106 P. aeruginosa cells. (A) At 24 h postinfection, the percentage of lung-infiltrating neutrophils of live cells was measured by flow cytometry. (B) CFU of P. aeruginosa recovered from lungs 24 h postinfection. Data show medians and interquartile ranges of representative data from 2 experiments (n = 5 to 10 per group in each experiment). Asterisks indicate P values (*, P < 0.05; **, P < 0.01).
FIG 3
FIG 3
FcRn shapes the prevalence of IgG isotypes in lung after M. tuberculosis infection. WT and fcgrt−/− animals were subjected to aerosol infection with M. tuberculosis. (A) Bioplex analysis of immunoglobulin isotypes on day 28 postinfection in serum, lung tissue homogenate (Parenchyma), or bronchoalveolar lavage fluid (Lavage). Box and whisker plots show the means and interquartile and total ranges, and asterisks indicate P values (*, P < 0.05; **, P < 0.01; ***, P < 0.001). (B) Flow cytometry quantification of B220+ lymphocytes in lung. Panels A and B show pooled data from 2 or 3 replicate experiments per time point (n = 5 to 6 animals per group in each experiment). (C) Representative results of immunohistochemistry of infected WT lung sections performed on day 28 after infection revealing intracellular IgG2c (green) in addition to nuclear DAPI staining (blue). Scale bars, 100 μm (left and middle panels) and 30 μm (far right panel). (D) Median fluorescence intensity (MFI) of intracellular IgG2c measured by flow cytometry in various lung-resident and infiltrating immune cells on day 28 postinfection. Data are representative of the results from 2 experiments (n = 4 to 6 animals per group in each experiment).
FIG 4
FIG 4
FcRn regulation of IgG during tuberculosis favors infiltration of myeloid cells and restricts T cell priming. Leukocyte infiltration in WT and fcgrt−/− lung was analyzed by flow cytometry after aerosol infection with M. tuberculosis. (A) Quantification of the indicated myeloid cell subsets postinfection. (B) Quantification of the number of innate immune cells in the lung that were positive for GFP 28 days after infection with M. tuberculosis expressing GFP (MTBGFP+) compared to the number in the lung of control animals infected with nonfluorescent H37Rv. (C) Quantification of the number of CD44hi CD69+-expressing CD3+ CD4+ or CD3+ CD8+ T cells in lung at the indicated time points before and after infection. (D) A total of 1 × 106 transgenic TCR P25 CD4 T cells stained with carboxyfluorescein succinimidyl ester (CFSE) were intravenously transferred into M. tuberculosis-infected WT and fcgrt−/− mice on day 12 following infection. On day 15 postinfection, the proportion of transferred T cells that underwent cell division was measured as shown on the representative flow cytometry histograms. All graphs show the median and interquartile range and cumulative individual data from 2 pooled experiments where n = 5 animals per experiment, except panel D, which shows results from one experiment of two performed. Asterisks indicate the P value (*, P < 0.05).
FIG 5
FIG 5
FcRn transiently affects disease progression in the lung during tuberculosis. WT and fcgrt−/− mice were subjected to aerosol infection with M. tuberculosis. (A) CFU levels in lung were measured at various time points. (B) CFU levels in spleen and liver were measured at day 28 after infection. (C) Quantification of parenchymal M. tuberculosis was performed by plating total lung homogenates following bronchoalveolar lavage 1 day after infection. Graphs show cumulative data and the medians and interquartile ranges of the results of 2 experiments (n = 4 to 9 per group in each experiment). Asterisks indicate P values (*, P < 0.05; ****, P < 0.0001). (D and E) Representative histology sections of lung at day 28 postinfection showing the results of staining with hematoxylin and eosin to reveal immune infiltrated areas (D) and of immunofluorescent staining for myeloperoxidase (red) and cell nuclei (blue) (E). Scale bars, 1,000 μm.
FIG 6
FIG 6
Stromal and immune cells expressing FcRn contribute to transient uncontrolled bacterial growth in tuberculosis. Lethally irradiated WT and fcgrt−/− mice were reconstituted with WT or fcgrt−/− bone marrow to create mixed or control chimeric mice, which were subjected to aerosol infection with M. tuberculosis and sacrificed 28 days later for analysis. (A) Specific IgG in serum and lung homogenate was quantified by ELISA. KO, knockout. (B) Ly6G+ CD11b+ neutrophils were measured as a proportion of live cells by flow cytometry. (C) Bacterial loads were quantified in the lung and spleen. Graphs show the medians and interquartile ranges of representative results from two experiments (n = 4 to 6 per group in each experiment). Asterisks indicate the P value (*, P < 0.05).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Sutherland DB, Suzuki K, Fagarasan S. 2016. Fostering of advanced mutualism with gut microbiota by immunoglobulin A. Immunol Rev 270:20–31. doi:10.1111/imr.12384. - DOI - PubMed
    1. Blumberg RS, Koss T, Story CM, Barisani D, Polischuk J, Lipin A, Pablo L, Green R, Simister NE. 1995. A major histocompatibility complex class I-related Fc receptor for IgG on rat hepatocytes. J Clin Invest 95:2397–2402. doi:10.1172/JCI117934. - DOI - PMC - PubMed
    1. Weflen AW, Baier N, Tang QJ, Van den Hof M, Blumberg RS, Lencer WI, Massol RH. 2013. Multivalent immune complexes divert FcRn to lysosomes by exclusion from recycling sorting tubules. Mol Biol Cell 24:2398–2405. doi:10.1091/mbc.E13-04-0174. - DOI - PMC - PubMed
    1. Yoshida M, Kobayashi K, Kuo TT, Bry L, Glickman JN, Claypool SM, Kaser A, Nagaishi T, Higgins DE, Mizoguchi E, Wakatsuki Y, Roopenian DC, Mizoguchi A, Lencer WI, Blumberg RS. 2006. Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria. J Clin Invest 116:2142–2151. doi:10.1172/JCI27821. - DOI - PMC - PubMed
    1. Stapleton NM, Einarsdottir HK, Stemerding AM, Vidarsson G. 2015. The multiple facets of FcRn in immunity. Immunol Rev 268:253–268. doi:10.1111/imr.12331. - DOI - PubMed

MeSH terms