Article | Published:

Frequencies of circulating regulatory TIGIT+CD38+ effector T cells correlate with the course of inflammatory bowel disease

Mucosal Immunologyvolume 12pages154163 (2019) | Download Citation

Subjects

Abstract

Disease heterogeneity hampers achieving long-term disease remission in inflammatory bowel disease (IBD). Monitoring ongoing tissue-localized regulatory and inflammatory T-cell responses in peripheral blood would empower disease classification. We determined whether regulatory and inflammatory phenotypes of circulating CD38+ effector (CD62LnegCD4+) T cells, a population enriched for cells with mucosal antigen specificity, classify disease course in pediatric IBD patients. In healthy individuals, circulating CD38+ effector T cells had a predominant regulatory component with lower frequencies of IFNγ-secreting T cells, higher frequencies of IL-10-secreting T cells and higher frequencies of inhibitory molecule T-cell immunoglobulin and ITIM domain+ (TIGIT) cells than CD38neg effector T cells. TIGIT expression was stable upon stimulation and marked CD38+ T cells with inhibitory properties. In IBD patients with active intestinal inflammation this predominant regulatory component was lost: circulating CD38+ effector T cells had increased activated CD25+CD45RAneg and decreased TIGIT+ cell frequencies. TIGIT percentages below 25% before treatment associated with shorter duration of clinical remission. In conclusion, phenotypic changes in circulating CD38+ effector T cells, in particular the frequency of TIGIT+ cells, classify pediatric IBD patients and predict severity of disease course. These findings have relevance for IBD and can be exploited in graft-versus-host-disease and checkpoint inhibitor-induced inflammation in cancer.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Sartor, R. B. Pathogenesis and immune mechanisms of chronic inflammatory bowel diseases. Am. J. Gastroenterol. 92(12 Suppl), 5S–11S (1997).

  2. 2.

    Maul, J. et al. Peripheral and intestinal regulatory CD4+CD25(high) T cells in inflammatory bowel disease. Gastroenterology 128, 1868–1878 (2005).

  3. 3.

    Ban, H. et al. Increased number of FoxP3+CD4+regulatory T cells in inflammatory bowel disease. Mol. Med. Rep. 1, 647–650 (2008).

  4. 4.

    Li, Z. et al. Restoration of Foxp3+regulatory T-cell subsets and Foxp3- type 1 regulatory-like T cells in inflammatory bowel diseases during anti-tumor necrosis factor therapy. Inflamm. Bowel Dis. 21, 2418–2428 (2015).

  5. 5.

    Veltkamp, C. et al. Apoptosis of regulatory T lymphocytes is increased in chronic inflammatory bowel disease and reversed by anti-TNFalpha treatment. Gut 60, 1345–1353 (2011).

  6. 6.

    Guidi, L. et al. FOXP3(+) T regulatory cell modifications in inflammatory bowel disease patients treated with anti-TNFalpha agents. Biomed. Res. Int. 2013, 286368 (2013).

  7. 7.

    La Scaleia, R. et al. Peripheral and intestinal CD4+T cells with a regulatory phenotype in pediatric patients with inflammatory bowel disease. J. Pediatr. Gastroenterol. Nutr. 51, 563–572 (2010).

  8. 8.

    du Pre, M. F. et al. CD62L(neg)CD38(+) expression on circulating CD4(+) T cells identifies mucosally differentiated cells in protein fed mice and in human celiac disease patients and controls. Am. J. Gastroenterol. 106, 1147–1159 (2011).

  9. 9.

    Deaglio, S. et al. Human CD38 and its ligand CD31 define a unique lamina propria T lymphocyte signaling pathway. FASEB J. 15, 580–582 (2001).

  10. 10.

    Schneider, M. et al. CD38 is expressed on inflammatory cells of the intestine and promotes intestinal inflammation. PLoS One. 10, e0126007 (2015).

  11. 11.

    Wang, J., Ioan-Facsinay, A., van der Voort, E. I., Huizinga, T. W. & Toes, R. E. Transient expression of FOXP3 in human activated nonregulatory CD4+T cells. Eur. J. Immunol. 37, 129–138 (2007).

  12. 12.

    Miyara, M. et al. Functional delineation and differentiation dynamics of human CD4+T cells expressing the FoxP3 transcription factor. Immunity 30, 899–911 (2009).

  13. 13.

    Lord, J. D., Shows, D. M., Chen, J. & Thirlby, R. C. Human blood and mucosal regulatory T cells express activation markers and inhibitory receptors in inflammatory bowel disease. PLoS One 10, e0136485 (2015).

  14. 14.

    Joller, N. et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 40, 569–581 (2014).

  15. 15.

    Burton, B. R. et al. Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy. Nat. Commun. 5, 4741 (2014).

  16. 16.

    Yu, X. et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat. Immunol. 10, 48–57 (2009).

  17. 17.

    Hastings, W. D. et al. TIM-3 is expressed on activated human CD4+T cells and regulates Th1 and Th17 cytokines. Eur. J. Immunol. 39, 2492–2501 (2009).

Download references

Acknowledgements

M.J. was supported by the Netherlands Organisation for Scientific Research grant 2013/09420/BOO; C.M., L.F.dR., and S.V. were funded by Dutch Sophia Research Foundation research grants S13-19, 671 and S14-17 respectively. Crocokids and the European Crohn’s and Colitis Organisation financially supported experimental costs. We thank Jessie M. Hulst and Barbara A.E. de Koning for contributing patient samples and Merel A. van Pieterson and Martha A. van Gaalen for study coordination. We thank the IBD patients and their families for participating and supporting our research.

Author information

Affiliations

  1. Laboratory of Pediatrics, division Gastroenterology and Nutrition, Erasmus University Medical Center-Sophia Children’s Hospital, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands

    • Maria E. Joosse
    • , Celia L. Menckeberg
    • , Lilian F. de Ruiter
    • , H. (Rolien) C. Raatgeep
    • , Lisette A. van Berkel
    • , Ytje Simons-Oosterhuis
    • , Irma Tindemans
    • , Sharon Veenbergen
    •  & Janneke N. Samsom
  2. Department of Pulmonology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands

    • A. (Femke) M. Muskens
    •  & Rudi W. Hendriks
  3. Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands

    • Remco M. Hoogenboezem
    •  & Tom Cupedo
  4. Department of Pediatric Gastroenterology, Erasmus University Medical Center-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands

    • Lissy de Ridder
    •  & Johanna C. Escher

Authors

  1. Search for Maria E. Joosse in:

  2. Search for Celia L. Menckeberg in:

  3. Search for Lilian F. de Ruiter in:

  4. Search for H. (Rolien) C. Raatgeep in:

  5. Search for Lisette A. van Berkel in:

  6. Search for Ytje Simons-Oosterhuis in:

  7. Search for Irma Tindemans in:

  8. Search for A. (Femke) M. Muskens in:

  9. Search for Rudi W. Hendriks in:

  10. Search for Remco M. Hoogenboezem in:

  11. Search for Tom Cupedo in:

  12. Search for Lissy de Ridder in:

  13. Search for Johanna C. Escher in:

  14. Search for Sharon Veenbergen in:

  15. Search for Janneke N. Samsom in:

Contributions

M.J. and J.S. contributed to study concept and design, interpretation of data, and drafting of the manuscript. M.J. designed, conducted, and analyzed experiments. R.H., T.C., and S.V. contributed to sequencing data analysis and interpretation. C.M., L.F.dR., H.R., L.vB., Y.S., and F.M. performed experiments and data analysis. R.H., T.C., and S.V. provided important intellectual content. L.dR. and J.C.E. contributed important intellectual content and contributed the patient-sample collection. J.S. conceived the project, obtained funding and had full responsibility for the study.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Janneke N. Samsom.

Electronic supplementary material

About this article

Publication history

Received

Revised

Accepted

Published

Issue Date

DOI

https://doi.org/10.1038/s41385-018-0078-4