Variants in human CD48 lead to impaired T-cell immunity and increased inflammation

Samantha Milanesi; Tiziana Lorenzini; Tommaso Marchetti; Diana Tintor; Raquel Planas; Ola Sabet; Lars Malmström; Sudip Acharya; Carson D. Williams; Zoe E. Manning; Jack H. Roser; Angelica C. Ehler; Michael Huber; Seraina Prader; Stefano Vavassori; Cullen M. Dutmer; Jordan K. Abbott; Jana Pachlopnik Schmid

doi:10.1172/JCI191340

¹Pediatric Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

²Department of Cell Biology, Physiology and Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Barcelona, Spain

³Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Aurora, United States of America

⁴Institute of Medical Virology, University of Zurich, Zurich, Switzerland

Find articles by Milanesi, S. in: PubMed | Google Scholar

¹Pediatric Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

²Department of Cell Biology, Physiology and Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Barcelona, Spain

³Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Aurora, United States of America

⁴Institute of Medical Virology, University of Zurich, Zurich, Switzerland

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¹Pediatric Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

²Department of Cell Biology, Physiology and Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Barcelona, Spain

³Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Aurora, United States of America

⁴Institute of Medical Virology, University of Zurich, Zurich, Switzerland

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¹Pediatric Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

²Department of Cell Biology, Physiology and Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Barcelona, Spain

³Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Aurora, United States of America

⁴Institute of Medical Virology, University of Zurich, Zurich, Switzerland

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¹Pediatric Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

²Department of Cell Biology, Physiology and Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Barcelona, Spain

³Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Aurora, United States of America

⁴Institute of Medical Virology, University of Zurich, Zurich, Switzerland

Find articles by Planas, R. in: PubMed | Google Scholar

¹Pediatric Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

²Department of Cell Biology, Physiology and Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Barcelona, Spain

³Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Aurora, United States of America

⁴Institute of Medical Virology, University of Zurich, Zurich, Switzerland

Find articles by Sabet, O. in: PubMed | Google Scholar

¹Pediatric Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

²Department of Cell Biology, Physiology and Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Barcelona, Spain

³Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Aurora, United States of America

⁴Institute of Medical Virology, University of Zurich, Zurich, Switzerland

Find articles by Malmström, L. in: PubMed | Google Scholar

¹Pediatric Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

²Department of Cell Biology, Physiology and Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Barcelona, Spain

³Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Aurora, United States of America

⁴Institute of Medical Virology, University of Zurich, Zurich, Switzerland

Find articles by Acharya, S. in: PubMed | Google Scholar

¹Pediatric Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

²Department of Cell Biology, Physiology and Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Barcelona, Spain

³Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Aurora, United States of America

⁴Institute of Medical Virology, University of Zurich, Zurich, Switzerland

Find articles by Williams, C. in: PubMed | Google Scholar

¹Pediatric Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

²Department of Cell Biology, Physiology and Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Barcelona, Spain

³Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Aurora, United States of America

⁴Institute of Medical Virology, University of Zurich, Zurich, Switzerland

Find articles by Manning, Z. in: PubMed | Google Scholar

¹Pediatric Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

²Department of Cell Biology, Physiology and Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Barcelona, Spain

³Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Aurora, United States of America

⁴Institute of Medical Virology, University of Zurich, Zurich, Switzerland

Find articles by Roser, J. in: PubMed | Google Scholar

¹Pediatric Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

²Department of Cell Biology, Physiology and Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Barcelona, Spain

³Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Aurora, United States of America

⁴Institute of Medical Virology, University of Zurich, Zurich, Switzerland

Find articles by Ehler, A. in: PubMed | Google Scholar

¹Pediatric Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

²Department of Cell Biology, Physiology and Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Barcelona, Spain

³Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Aurora, United States of America

⁴Institute of Medical Virology, University of Zurich, Zurich, Switzerland

Find articles by Huber, M. in: PubMed | Google Scholar |

¹Pediatric Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

²Department of Cell Biology, Physiology and Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Barcelona, Spain

³Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Aurora, United States of America

⁴Institute of Medical Virology, University of Zurich, Zurich, Switzerland

Find articles by Prader, S. in: PubMed | Google Scholar

¹Pediatric Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

²Department of Cell Biology, Physiology and Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Barcelona, Spain

³Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Aurora, United States of America

⁴Institute of Medical Virology, University of Zurich, Zurich, Switzerland

Find articles by Vavassori, S. in: PubMed | Google Scholar

¹Pediatric Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

²Department of Cell Biology, Physiology and Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Barcelona, Spain

³Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Aurora, United States of America

⁴Institute of Medical Virology, University of Zurich, Zurich, Switzerland

Find articles by Dutmer, C. in: PubMed | Google Scholar

¹Pediatric Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

²Department of Cell Biology, Physiology and Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Barcelona, Spain

³Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Aurora, United States of America

⁴Institute of Medical Virology, University of Zurich, Zurich, Switzerland

Find articles by Abbott, J. in: PubMed | Google Scholar

¹Pediatric Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

²Department of Cell Biology, Physiology and Immunology, University of Zurich and the Children’s Research Center, University Children’s Hospital Zurich, Barcelona, Spain

³Department of Pediatrics, Section of Allergy and Immunology, University of Colorado School of Medicine, Aurora, United States of America

⁴Institute of Medical Virology, University of Zurich, Zurich, Switzerland

Find articles by Pachlopnik Schmid, J. in: PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI191340.
Copyright © 2026, Milanesi et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published April 15, 2026 - Version history

CD48 is a surface molecule with immunoregulatory functions. Following our initial report of a patient with a de novo heterozygous variant at amino acid S220 in the CD48 gene, we describe a second, unrelated patient with similar features of immune dysregulation and a missense change affecting the same residue. To further elucidate the specific pathogenic mechanisms of the identified variants, we reviewed patient records, analyzed patient-derived cells, and employed complementary in vitro and in vivo model systems, including transfected cell lines and CD48-deficient mice. We demonstrate that the variants are associated with altered distribution of CD48, characterized by diminished CD48 surface expression, intracellular retention, and activation of endoplasmic reticulum stress signaling. Patient T cells display increased susceptibility to apoptosis, reduced antiviral responses, and enhanced inflammation. Both patients exhibit T-cell lymphopenia, a restricted TCR repertoire diversity, and oligoclonal expansions consistent with antigen-driven selection. In parallel, virally-infected CD48-deficient mice recapitulate key aspects of the human phenotype, including delayed antiviral immune responses, impaired viral clearance and pronounced inflammation. We conclude that identified variants compromise CD48 cell-surface localization, impair T-cell survival and function, and predispose to inflammation, thereby highlighting the role of CD48 in immune regulation and the prevention of excessive inflammation.

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Variants in human CD48 lead to impaired T-cell immunity and increased inflammation

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