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αEβ7 Integrin Identifies Subsets of Pro-Inflammatory Colonic CD4+ T Lymphocytes in Ulcerative Colitis.
J Crohns Colitis 2017; 11(5):610-620JC

Abstract

Background and Aims

The αEβ7 integrin is crucial for retention of T lymphocytes at mucosal surfaces through its interaction with E-cadherin. Pathogenic or protective functions of these cells during human intestinal inflammation, such as ulcerative colitis [UC], have not previously been defined, with understanding largely derived from animal model data. Defining this phenotype in human samples is important for understanding UC pathogenesis and is of translational importance for therapeutic targeting of αEβ7-E-cadherin interactions.

Methods

αEβ7+ and αEβ7- colonic T cell localization, inflammatory cytokine production and expression of regulatory T cell-associated markers were evaluated in cohorts of control subjects and patients with active UC by immunohistochemistry, flow cytometry and real-time PCR of FACS-purified cell populations.

Results

CD4+αEβ7+ T lymphocytes from both healthy controls and UC patients had lower expression of regulatory T cell-associated genes, including FOXP3, IL-10, CTLA-4 and ICOS in comparison with CD4+αEβ7- T lymphocytes. In UC, CD4+αEβ7+ lymphocytes expressed higher levels of IFNγ and TNFα in comparison with CD4+αEβ7- lymphocytes. Additionally the CD4+αEβ7+ subset was enriched for Th17 cells and the recently described Th17/Th1 subset co-expressing both IL-17A and IFNγ, both of which were found at higher frequencies in UC compared to control.

Conclusion

αEβ7 integrin expression on human colonic CD4+ T cells was associated with increased production of pro-inflammatory Th1, Th17 and Th17/Th1 cytokines, with reduced expression of regulatory T cell-associated markers. These data suggest colonic CD4+αEβ7+ T cells are pro-inflammatory and may play a role in UC pathobiology.

Authors+Show Affiliations

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK.Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK. Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.Research & Early Development, Genentech, South San Francisco, CA 94080, USA.Peter Gorer Department of Immunobiology, King's College London, London SE1 9RT, UK. London Research Institute, Cancer Research UK, London WC2, UK.Department of Cellular Pathology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK.Peter Gorer Department of Immunobiology, King's College London, London SE1 9RT, UK. Department of Gastroenterology, Guys and St Thomas' NHS Foundation Trust, London SE1 7EH, UK.Research & Early Development, Genentech, South San Francisco, CA 94080, USA.Research & Early Development, Genentech, South San Francisco, CA 94080, USA.Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK.Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.Research & Early Development, Genentech, South San Francisco, CA 94080, USA.Peter Gorer Department of Immunobiology, King's College London, London SE1 9RT, UK. London Research Institute, Cancer Research UK, London WC2, UK.Research & Early Development, Genentech, South San Francisco, CA 94080, USA.Research & Early Development, Genentech, South San Francisco, CA 94080, USA.Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28453768

Citation

Lamb, Christopher A., et al. "ΑEβ7 Integrin Identifies Subsets of Pro-Inflammatory Colonic CD4+ T Lymphocytes in Ulcerative Colitis." Journal of Crohn's & Colitis, vol. 11, no. 5, 2017, pp. 610-620.
Lamb CA, Mansfield JC, Tew GW, et al. ΑEβ7 Integrin Identifies Subsets of Pro-Inflammatory Colonic CD4+ T Lymphocytes in Ulcerative Colitis. J Crohns Colitis. 2017;11(5):610-620.
Lamb, C. A., Mansfield, J. C., Tew, G. W., Gibbons, D., Long, A. K., Irving, P., ... Kirby, J. A. (2017). ΑEβ7 Integrin Identifies Subsets of Pro-Inflammatory Colonic CD4+ T Lymphocytes in Ulcerative Colitis. Journal of Crohn's & Colitis, 11(5), pp. 610-620. doi:10.1093/ecco-jcc/jjw189.
Lamb CA, et al. ΑEβ7 Integrin Identifies Subsets of Pro-Inflammatory Colonic CD4+ T Lymphocytes in Ulcerative Colitis. J Crohns Colitis. 2017 May 1;11(5):610-620. PubMed PMID: 28453768.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - αEβ7 Integrin Identifies Subsets of Pro-Inflammatory Colonic CD4+ T Lymphocytes in Ulcerative Colitis. AU - Lamb,Christopher A, AU - Mansfield,John C, AU - Tew,Gaik W, AU - Gibbons,Deena, AU - Long,Anna K, AU - Irving,Peter, AU - Diehl,Lauri, AU - Eastham-Anderson,Jeff, AU - Price,Maria B, AU - O'Boyle,Graeme, AU - Jones,David E J, AU - O'Byrne,Sharon, AU - Hayday,Adrian, AU - Keir,Mary E, AU - Egen,Jackson G, AU - Kirby,John A, PY - 2016/05/16/received PY - 2016/10/19/accepted PY - 2017/4/29/entrez PY - 2017/4/30/pubmed PY - 2018/3/9/medline KW - CD103 KW - CD4+ T cell KW - Th1 KW - Th17 KW - Th17/1 KW - Treg KW - cytokine KW - effector T cell KW - etrolizumab KW - helper T cell KW - inflammatory bowel disease KW - intraepithelial lymphocytes KW - mucosal immunology KW - regulatory T cell KW - ulcerative colitis KW - αEβ7 integrin SP - 610 EP - 620 JF - Journal of Crohn's & colitis JO - J Crohns Colitis VL - 11 IS - 5 N2 - Background and Aims: The αEβ7 integrin is crucial for retention of T lymphocytes at mucosal surfaces through its interaction with E-cadherin. Pathogenic or protective functions of these cells during human intestinal inflammation, such as ulcerative colitis [UC], have not previously been defined, with understanding largely derived from animal model data. Defining this phenotype in human samples is important for understanding UC pathogenesis and is of translational importance for therapeutic targeting of αEβ7-E-cadherin interactions. Methods: αEβ7+ and αEβ7- colonic T cell localization, inflammatory cytokine production and expression of regulatory T cell-associated markers were evaluated in cohorts of control subjects and patients with active UC by immunohistochemistry, flow cytometry and real-time PCR of FACS-purified cell populations. Results: CD4+αEβ7+ T lymphocytes from both healthy controls and UC patients had lower expression of regulatory T cell-associated genes, including FOXP3, IL-10, CTLA-4 and ICOS in comparison with CD4+αEβ7- T lymphocytes. In UC, CD4+αEβ7+ lymphocytes expressed higher levels of IFNγ and TNFα in comparison with CD4+αEβ7- lymphocytes. Additionally the CD4+αEβ7+ subset was enriched for Th17 cells and the recently described Th17/Th1 subset co-expressing both IL-17A and IFNγ, both of which were found at higher frequencies in UC compared to control. Conclusion: αEβ7 integrin expression on human colonic CD4+ T cells was associated with increased production of pro-inflammatory Th1, Th17 and Th17/Th1 cytokines, with reduced expression of regulatory T cell-associated markers. These data suggest colonic CD4+αEβ7+ T cells are pro-inflammatory and may play a role in UC pathobiology. SN - 1876-4479 UR - https://www.unboundmedicine.com/medline/citation/28453768/αEβ7_Integrin_Identifies_Subsets_of_Pro_Inflammatory_Colonic_CD4+_T_Lymphocytes_in_Ulcerative_Colitis_ L2 - https://academic.oup.com/ecco-jcc/article-lookup/doi/10.1093/ecco-jcc/jjw189 DB - PRIME DP - Unbound Medicine ER -