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CXCR5+PD-1++ CD4+ T cells colonize infant intestines early in life and promote B cell maturation

Cellular & Molecular Immunology volume 20, pages 201–213 (2023)Cite this article

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Abstract

Gastrointestinal infections are a major cause for serious clinical complications in infants. The induction of antibody responses by B cells is critical for protective immunity against infections and requires CXCR5+PD-1++ CD4+ T cells (TFH cells). We investigated the ontogeny of CXCR5+PD-1++ CD4+ T cells in human intestines. While CXCR5+PD-1++ CD4+ T cells were absent in fetal intestines, CXCR5+PD-1++ CD4+ T cells increased after birth and were abundant in infant intestines, resulting in significant higher numbers compared to adults. These findings were supported by scRNAseq analyses, showing increased frequencies of CD4+ T cells with a TFH gene signature in infant intestines compared to blood. Co-cultures of autologous infant intestinal CXCR5+PD-1+/−CD4+ T cells with B cells further demonstrated that infant intestinal TFH cells were able to effectively promote class switching and antibody production by B cells. Taken together, we demonstrate that functional TFH cells are numerous in infant intestines, making them a promising target for oral pediatric vaccine strategies.

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Acknowledgements

The authors would like to thank all donors for participating in this study; Dr. Weijer, Mrs. Voordouw, Mrs. Siteur-van Rijnstra, and the Bloemenhove Clinic (Heemstede, the Netherlands) for collecting and providing fetal tissues. The authors also thank the FACS Core facility members of the Leibniz Institute of Virology (LIV) for their support, Mr. Arne Düsedau and Mrs. Jana Henessen. This study is supported by the Innovative Antiviral Therapy Program, Leibniz Institute of Virology (LIV), the German Center for Infection Research (DZIF), EFRE 2014-2020 REACT-EU, Dutch Digestive Fund (MLDS CDG 15-02), Deutsche Forschungsgemeinschaft (BU 3630/2-1) and Hüet Roëll Foundation. MK is supported by a Walter Benjamin Fellowship of the Deutsche Forschungsgemeinschaft (KA5554/1-1, KA5554/1-2). The Leibniz Institute of Virology is supported by the Free and Hanseatic City of Hamburg and the Federal Ministry of Health.

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Author notes

  1. These authors contributed equally: Ana Jordan-Paiz, Glòria Martrus, Fenja L. Steinert.

Authors and Affiliations

  1. Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, 20251, Germany

    Ana Jordan-Paiz, Glòria Martrus, Fenja L. Steinert, Adrian F. Sagebiel, Anne Rechtien, Martin E. Baumdick, Johannes M. Jung, Kimberly J. Möller, Lucy Wegner, Cordula Grüttner, Roland Thünauer, Marcus Altfeld & Madeleine J. Bunders

  2. University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany

    Fenja L. Steinert, Kimberly J. Möller & Lucy Wegner

  3. Institute of Neuroimmunology and Multiple Sclerosis, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, 20251, Germany

    Max Kaufmann & Manuel A. Friese

  4. Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany

    Adrian F. Sagebiel, Daniel Perez & Nathaniel Melling

  5. Department of Experimental Immunology; Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, 1105 AZ, The Netherlands

    Renée R. C. E. Schreurs & Teunis B. H. Geijtenbeek

  6. Department of Pediatrics, Emma Children’s Hospital, Amsterdam University Medical Center, University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, 1105 AZ, The Netherlands

    Renée R. C. E. Schreurs & Johannes B. van Goudoever

  7. I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany

    Anne Rechtien

  8. Partner Site Hamburg-Lübeck-Borstel-Riems, German Center for Infection Research (DZIF), Hamburg, 20246, Germany

    Anne Rechtien

  9. University of Bordeaux, Institut National de la Santé et de la Recherche Médicale, Bordeaux Population Health Research Center UMR1219 and INRIA SISTM Team, Bordeaux, 33000, France

    Laura Richert

  10. Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany

    Jennifer Schroeder-Schwarz & Udo Schumacher

  11. Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, 1105 AZ, The Netherlands

    Steven T. Pals

  12. Department of Rheumatology and Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, 1007 MB, The Netherlands

    Paul L. Klarenbeek

  13. Amsterdam Rheumatology & Immunology Center, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, 1105 AZ, The Netherlands

    Paul L. Klarenbeek

  14. Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany

    Christian Tomuschat & Konrad Reinshagen

  15. Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany

    Guido Sauter

  16. Department of Pediatric Surgery, Altona Children’s Hospital, Hamburg, 22763, Germany

    Ingo Königs

  17. III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany

    Madeleine J. Bunders

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  1. Ana Jordan-Paiz
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Contributions

AJP, GM, FLS, and MJB designed the experiments. AJP, GM, FLS, MK, AFS, RRCES, AR, MEB, CG, RT, JSS, JBG, TBH, MA, US, STP, MAF and PLK contributed to experiments and interpretation of data. AJP, FLS, AFS, RRCES, JMJ, KJM, LW, STP, IK, DP, KR, CT, GS and NM contributed to collection of tissue samples. LR supported the statistical analysis. AJP, GM, FLS, LR, MAF, MK and PLK performed the data analyses. AJP, GM and MJB wrote the manuscript with input from all authors, who revised the manuscript. MJB supervised the study.

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Correspondence to Madeleine J. Bunders.

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Jordan-Paiz, A., Martrus, G., Steinert, F.L. et al. CXCR5+PD-1++ CD4+ T cells colonize infant intestines early in life and promote B cell maturation. Cell Mol Immunol 20, 201–213 (2023). https://doi.org/10.1038/s41423-022-00944-4

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