Epithelial cells prime the immune response to an array of gut‐derived commensals towards a tolerogenic phenotype through distinct actions of thymic stromal lymphopoietin and transforming growth factor‐β
Open accessAbstract
Humans and other mammals coexist with a diverse array of microbes colonizing the intestine, termed the microflora. The relationship is symbiotic, with the microbes benefiting from a stable environment and nutrient supply, and the host gaining competitive exclusion of pathogens and continuously maintenance of the gut immune homeostasis. Here we report novel crosstalk mechanisms between the human enterocyte cell line, Caco2, and underlying human monocyte-derived DC in a transwell model where Gram-positive (G+) commensals prevent Toll-like receptor-4 (TLR4)-dependent Escherichia coli-induced semimaturation in a TLR2-dependent fashion. These findings add to our understanding of the hypo-responsiveness of the gut epithelium towards the microflora. Gut DC posses a more tolerogenic phenotype than conventional DC. Here we show that Caco2 spent medium (SM) induces tolerogenic DC with lower expression of maturation markers, interleukin (IL)-12p70, and tumour necrosis factor-alpha when matured with G+ and Gram-negative (G-) commensals, while IL-10 production is enhanced in DC upon encountering G+ commensals and reduced upon encountering G- bacteria. The Caco2 SM-induced tolerogenic phenotype is also seen in DC priming of naive T cells with elevated levels of transforming growth factor-beta (TGF-beta) and markedly reduced levels of bacteria-induced interferon-gamma production. Caco2 cell production of IL-8, thymic stromal lymphopoietin (TSLP) and TGF-beta increases upon microbial stimulation in a strain dependent manner. TSLP and TGF-beta co-operate in inducing the tolerogenic DC phenotype but other mediators might be involved.
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Probiotic interventions promote tolerogenicity, can replace pathogenic strains, and reduce inflammation, so T cell depletion and senescence could be reduced in HIV patients.
“Probiotic interventions have become an interesting therapeutic target for HIV patients because they promote tolerogenicity [169], can replace pathogenic strains, and reduce inflammation [170]; consequently, T cell depletion and senescence could be reduced.”
From The Potential Impact of Probiotics on Human Health: An Update on Their Health-Promoting Properties (2024) · cites this paper as [169]
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Cites
Rescigno, M., Urbano, M., Valzasina, B., Francolini, M., Rotta, G., Bonasio, R., Granucci, F., Kraehenbuhl, J.-P., & Ricciardi‐Castagnoli, P. (2001) · Nature Immunology · doi:10.1038/86373 · Cited by 2,554 · see citing works
Pinto, M. (1983) · HAL · Cited by 1,752 · see citing works
CX 3 CR1-Mediated Dendritic Cell Access to the Intestinal Lumen and Bacterial Clearance
Niess, J. H., Brand, S., Gu, X., Landsman, L., Jung, S., McCormick, B. A., Vyas, J. M., Boes, M. L., Ploegh, H. L., Fox, J. G., et al. (2005) · Science · doi:10.1126/science.1102901 · Cited by 1,609 · see citing works
Ott, S. J., Musfeldt, M., Wenderoth, D. F., Hampe, J., Brant, O., Fölsch, U. R., Timmis, K. N., & Schreiber, S. (2004) · Gut · doi:10.1136/gut.2003.025403 · Cited by 1,311 · see citing works
Induction of tolerance by IL-10-treated dendritic cells
Steinbrink, K., Wölfl, M., Jonuleit, H., Knop, J., & Enk, A. H. (1997) · The Journal of Immunology · doi:10.4049/jimmunol.159.10.4772 · Cited by 1,245 · see citing works
Cario, E., & Podolsky, D. K. (2000) · Infection and Immunity · doi:10.1128/iai.68.12.7010-7017.2000 · Cited by 1,245 · see citing works
Napolitani, G., Rinaldi, A., Bertoni, F., Sallusto, F., & Lanzavecchia, A. (2005) · Nature Immunology · doi:10.1038/ni1223 · Cited by 1,156 · see citing works
TGF-β1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells
Marie, J. C., Letterio, J. J., Gavin, M. A., & Rudensky, A. Y. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20042276 · Cited by 986 · see citing works
Christensen, H. R., Frøkiær, H., & Pestka, J. J. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.1.171 · Cited by 905 · see citing works
Overview of gut flora and probiotics
Holzapfel, W. H., Haberer, P., Snel, J., Schillinger, U., & Veld, J. H. J. H. I. (1998) · International Journal of Food Microbiology · doi:10.1016/s0168-1605(98)00044-0 · Cited by 887 · see citing works
Rimoldi, M., Chieppa, M., Salucci, V., Avogadri, F., Sonzogni, A., Sampietro, G. M., Nespoli, A., Viale, G., Allavena, P., & Rescigno, M. (2005) · Nature Immunology · doi:10.1038/ni1192 · Cited by 815 · see citing works
Cario, E., Rosenberg, I. M., Brandwein, S. L., Beck, P. L., Reinecker, H., & Podolsky, D. K. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.2.966 · Cited by 751 · see citing works
Chieppa, M., Rescigno, M., Huang, A. Y.-C., & Germain, R. N. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20061884 · Cited by 711 · see citing works
Abreu, M. T., Vora, P., Faure, E., Thomas, L. S., Arnold, E. T., & Arditi, M. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.3.1609 · Cited by 681 · see citing works
Iwasaki, A., & Kelsall, B. L. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.190.2.229 · Cited by 636 · see citing works
Nakamura, K., Kitani, A., Fuss, I. J., Pedersen, A., Harada, N., Nawata, H., & Strober, W. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.2.834 · Cited by 630 · see citing works
Characteristics of Intestinal Dendritic Cells in Inflammatory Bowel Diseases
Hart, A. L., Al-Hassi, H. O., Rigby, R. J., Bell, S., Emmanuel, A. V., Knight, S. C., Kamm, M. A., & Stagg, A. J. (2005) · Gastroenterology · doi:10.1053/j.gastro.2005.05.013 · Cited by 562 · see citing works
Otte, J., Cario, E., & Podolsky, D. K. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.01.007 · Cited by 506 · see citing works
Tolerogenic dendritic cells: cytokine modulation comes of age
Rutella, S., Danese, S., & Leone, G. G. M. (2006) · Blood · doi:10.1182/blood-2006-03-006403 · Cited by 490 · see citing works
Haller, D., Bode, C., Hammes, W. P., Pfeifer, A. M. A., Schiffrin, E. J., & Blum, S. (2000) · Gut · doi:10.1136/gut.47.1.79 · Cited by 466 · see citing works
Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells
Lotz, M., Gütle, D., Walther, S., Ménard, S., Bogdan, C., & Hornef, M. W. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20050625 · Cited by 464 · see citing works
Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin
Pandey, A., Ozaki, K., Baumann, H., Levin, S. D., Puel, A., Farr, A. G., Ziegler, S. F., Leonard, W. J., & Lodish, H. F. (2000) · Nature Immunology · doi:10.1038/76923 · Cited by 446 · see citing works
Enterocyte TLR4 Mediates Phagocytosis and Translocation of Bacteria Across the Intestinal Barrier
Neal, M. D., Leaphart, C. L., Levy, R. M., Prince, J. M., Billiar, T. R., Watkins, S. C., Li, J., Çetin, S., Ford, H. R., Schreiber, A. D., et al. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.5.3070 · Cited by 434 · see citing works
Unique Functions of CD11b+, CD8α+, and Double-Negative Peyer’s Patch Dendritic Cells
Iwasaki, A., & Kelsall, B. L. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.8.4884 · Cited by 412 · see citing works
Huber, S., Schramm, C., Lehr, H. A., Mann, A., Schmitt, S., Becker, C., Protschka, M., Galle, P. R., Neurath, M. F., & Blessing, M. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.11.6526 · Cited by 390 · see citing works
Abreu, M. T., Arnold, E. T., Thomas, L. S., Gonsky, R., Zhou, Y., Hu, B., & Arditi, M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110333200 · Cited by 356 · see citing works
Cario, E., Brown, D., McKee, M. L., Lynch–Devaney, K., Gerken, G., & Podolsky, D. K. (2002) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64360-x · Cited by 301 · see citing works
Furrie, E., Macfarlane, S., Thomson, G., Macfarlane, G. T., & Microbiology & Gut Biology Group, T. T. &. T. B. (2005) · Immunology · doi:10.1111/j.1365-2567.2005.02200.x · Cited by 282 · see citing works
Thymic stromal lymphopoietin in normal and pathogenic T cell development and function
Ziegler, S. F., & Liu, Y.-J. (2006) · Nature Immunology · doi:10.1038/ni1360 · Cited by 234 · see citing works
Suzuki, M., Hisamatsu, T., & Podolsky, D. K. (2003) · Infection and Immunity · doi:10.1128/iai.71.6.3503-3511.2003 · Cited by 217 · see citing works
TGF-β1 regulation of dendritic cells
Strobl, H., & Knapp, W. (1999) · Microbes and Infection · doi:10.1016/s1286-4579(99)00256-7 · Cited by 216 · see citing works
Vaughan, E. E., de Vries, M. C., Zoetendal, E. G., Amor, K. B., Akkermans, A. D. L., & de Vos, W. M. (2002) · PubMed · Cited by 175 · see citing works
Clark, E. C., Hoare, C. J., Tanianis-Hughes, J., Carlson, G., & Warhurst, G. (2005) · Gastroenterology · doi:10.1053/j.gastro.2005.01.046 · Cited by 171 · see citing works
Rimoldi, M., Chieppa, M., Larghi, P., Vulcano, M., Allavena, P., & Rescigno, M. (2005) · Blood · doi:10.1182/blood-2004-11-4321 · Cited by 159 · see citing works
Kelsall, B. L., & Leon, F. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00292.x · Cited by 154 · see citing works
Gastrointestinal dendritic cells play a role in immunity, tolerance, and disease
Bilsborough, J., & Viney, J. L. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.01.028 · Cited by 137 · see citing works
Vaughan, E. E., de Vries, M. C., Zoetendal, E. G., Amor, K. B., Akkermans, A. D. L., & de Vos, W. M. (2002) · Antonie van Leeuwenhoek · doi:10.1023/a:1020672724450 · Cited by 136 · see citing works
Zeuthen, L., Christensen, H. R., & Frøkiær, H. (2006) · Clinical and Vaccine Immunology · doi:10.1128/cvi.13.3.365-375.2006 · Cited by 134 · see citing works
Self-citationDevelopment of intestinal M cells
Mach, J. A., Hshieh, T. T., Hsieh, D. J. ‐., Grubbs, N., & Chervonsky, A. V. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00281.x · Cited by 84 · see citing works
Modulation of dendritic cell phenotype and functionin an in vitro model of the intestinal epithelium
Butler, M., Ng, C., van Heel, D. A., Lombardi, G., Lechler, R. I., Playford, R. J., & Ghosh, S. K. (2006) · European Journal of Immunology · doi:10.1002/eji.200535497 · Cited by 75 · see citing works
Different cytokine response of primary colonic epithelial cells to commensal bacteria
Lan, J.-G. (2005) · World Journal of Gastroenterology · doi:10.3748/wjg.v11.i22.3375 · Cited by 60 · see citing works
Commensal bacteria do translocate across the intestinal barrier in surgical patients
Reddy, B. S., MacFie, J., Gatt, M., Macfarlane-Smith, L. R., Bitzopoulou, K., & Snelling, A. M. (2007) · Clinical Nutrition · doi:10.1016/j.clnu.2006.10.006 · Cited by 56 · see citing works
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Abreu, M. T. (2010) · Nature Reviews Immunology · doi:10.1038/nri2707 · Cited by 1,288 · see citing works
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Chiba, Y., Shida, K., Nagata, S., Wada, M., Bian, L., Wang, C., Shimizu, T., Yamashiro, Y., Kiyoshima‐Shibata, J., Nanno, M., et al. (2010) · Immunology · doi:10.1111/j.1365-2567.2009.03204.x · Cited by 102 · see citing works
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- Authors
- Zeuthen, L. H., Fink, L. N., & Frokiaer, H.
- Affiliations
- Technical University of Denmark (DK)
- Venue
- Immunology
- Publisher
- Wiley
- Published
- 2007-08-03
- Volume
- 123
- Issue
- 2
- Pages
- 197-208
- ISSN
- 0019-2805 (ISSN-L)
- 1365-2567
- PMC
- PMC2433297
- OpenAlex
- W1964788094
- Cited by
- 227
- References
- 42
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 9 · 2023: 8 · 2022: 11 · 2021: 7 · 2020: 6 · 2019: 9 · 2018: 10 · 2017: 20 · 2016: 7 · 2015: 18 · 2014: 17 · 2013: 18 · 2012: 11
- FWCI
- 5.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Immunology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Technical University of Denmark, DTU Orbit (Technical University of Denmark, DTU) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- gut commensals, tolerogenic dendritic cells, Caco-2 cells, monocyte-derived dendritic cells, Gram-positive bacteria, Gram-negative bacteria, TLR2, TLR4, Escherichia coli, IL-10, TGF-beta, thymic stromal lymphopoietin, interleukin-8, interferon-gamma, T cell priming, intestinal immune homeostasis
- MeSH terms
- Thymic Stromal Lymphopoietin, Bacteria, Cell Differentiation, Dendritic Cells, Epithelial Cells, Escherichia coli, Gram-Positive Bacteria, Humans, Immune Tolerance, Intestinal Mucosa, Lactobacillus, Symbiosis, Cytokines, Interleukin-8, Culture Media, Conditioned, Th1 Cells, Immunity, Mucosal, Caco-2 Cells, Toll-Like Receptor 2, Toll-Like Receptor 4, Transforming Growth Factor beta1
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