Neutrophil-enriched gene signature correlates with teplizumab therapy resistance in different stages of type 1 diabetes

Gabriele Sassi; Pierre Lemaitre; Laia Fernández Calvo; Francesca Lodi; Álvaro Cortés Calabuig; Samal Bissenova; Amber Wouters; Laure Degroote; Marijke Viaene; Niels Vandamme; Lauren Higdon; Peter S. Linsley; S. Alice Long; Chantal Mathieu; Conny Gysemans

doi:10.1172/JCI176403

¹Leuven Diabetes Lab, Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium

²VIB Laboratory of Translational Genetics, Leuven, Belgium

³Genomics Core Leuven, Centre for Human Genetics KU, Leuven, Belgium

⁴VIB Single Cell Core, Ghent, Belgium

⁵UCSF Diabetes Center, Immune Tolerance Network (ITN, San Francisco, United States of America

⁶Center for Systems Immunology, Benaroya Research Institute, Seattle, United States of America

⁷Center for Translational Immunology, Benaroya Research Institute, Seattle, United States of America

Find articles by Sassi, G. in: PubMed | Google Scholar

¹Leuven Diabetes Lab, Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium

²VIB Laboratory of Translational Genetics, Leuven, Belgium

³Genomics Core Leuven, Centre for Human Genetics KU, Leuven, Belgium

⁴VIB Single Cell Core, Ghent, Belgium

⁵UCSF Diabetes Center, Immune Tolerance Network (ITN, San Francisco, United States of America

⁶Center for Systems Immunology, Benaroya Research Institute, Seattle, United States of America

⁷Center for Translational Immunology, Benaroya Research Institute, Seattle, United States of America

Find articles by Lemaitre, P. in: PubMed | Google Scholar

¹Leuven Diabetes Lab, Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium

²VIB Laboratory of Translational Genetics, Leuven, Belgium

³Genomics Core Leuven, Centre for Human Genetics KU, Leuven, Belgium

⁴VIB Single Cell Core, Ghent, Belgium

⁵UCSF Diabetes Center, Immune Tolerance Network (ITN, San Francisco, United States of America

⁶Center for Systems Immunology, Benaroya Research Institute, Seattle, United States of America

⁷Center for Translational Immunology, Benaroya Research Institute, Seattle, United States of America

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

¹Leuven Diabetes Lab, Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium

²VIB Laboratory of Translational Genetics, Leuven, Belgium

³Genomics Core Leuven, Centre for Human Genetics KU, Leuven, Belgium

⁴VIB Single Cell Core, Ghent, Belgium

⁵UCSF Diabetes Center, Immune Tolerance Network (ITN, San Francisco, United States of America

⁶Center for Systems Immunology, Benaroya Research Institute, Seattle, United States of America

⁷Center for Translational Immunology, Benaroya Research Institute, Seattle, United States of America

Find articles by Lodi, F. in: PubMed | Google Scholar |

¹Leuven Diabetes Lab, Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium

²VIB Laboratory of Translational Genetics, Leuven, Belgium

³Genomics Core Leuven, Centre for Human Genetics KU, Leuven, Belgium

⁴VIB Single Cell Core, Ghent, Belgium

⁵UCSF Diabetes Center, Immune Tolerance Network (ITN, San Francisco, United States of America

⁶Center for Systems Immunology, Benaroya Research Institute, Seattle, United States of America

⁷Center for Translational Immunology, Benaroya Research Institute, Seattle, United States of America

Find articles by Cortés Calabuig, Á. in: PubMed | Google Scholar

¹Leuven Diabetes Lab, Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium

²VIB Laboratory of Translational Genetics, Leuven, Belgium

³Genomics Core Leuven, Centre for Human Genetics KU, Leuven, Belgium

⁴VIB Single Cell Core, Ghent, Belgium

⁵UCSF Diabetes Center, Immune Tolerance Network (ITN, San Francisco, United States of America

⁶Center for Systems Immunology, Benaroya Research Institute, Seattle, United States of America

⁷Center for Translational Immunology, Benaroya Research Institute, Seattle, United States of America

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

¹Leuven Diabetes Lab, Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium

²VIB Laboratory of Translational Genetics, Leuven, Belgium

³Genomics Core Leuven, Centre for Human Genetics KU, Leuven, Belgium

⁴VIB Single Cell Core, Ghent, Belgium

⁵UCSF Diabetes Center, Immune Tolerance Network (ITN, San Francisco, United States of America

⁶Center for Systems Immunology, Benaroya Research Institute, Seattle, United States of America

⁷Center for Translational Immunology, Benaroya Research Institute, Seattle, United States of America

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

¹Leuven Diabetes Lab, Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium

²VIB Laboratory of Translational Genetics, Leuven, Belgium

³Genomics Core Leuven, Centre for Human Genetics KU, Leuven, Belgium

⁴VIB Single Cell Core, Ghent, Belgium

⁵UCSF Diabetes Center, Immune Tolerance Network (ITN, San Francisco, United States of America

⁶Center for Systems Immunology, Benaroya Research Institute, Seattle, United States of America

⁷Center for Translational Immunology, Benaroya Research Institute, Seattle, United States of America

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

¹Leuven Diabetes Lab, Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium

²VIB Laboratory of Translational Genetics, Leuven, Belgium

³Genomics Core Leuven, Centre for Human Genetics KU, Leuven, Belgium

⁴VIB Single Cell Core, Ghent, Belgium

⁵UCSF Diabetes Center, Immune Tolerance Network (ITN, San Francisco, United States of America

⁶Center for Systems Immunology, Benaroya Research Institute, Seattle, United States of America

⁷Center for Translational Immunology, Benaroya Research Institute, Seattle, United States of America

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

¹Leuven Diabetes Lab, Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium

²VIB Laboratory of Translational Genetics, Leuven, Belgium

³Genomics Core Leuven, Centre for Human Genetics KU, Leuven, Belgium

⁴VIB Single Cell Core, Ghent, Belgium

⁵UCSF Diabetes Center, Immune Tolerance Network (ITN, San Francisco, United States of America

⁶Center for Systems Immunology, Benaroya Research Institute, Seattle, United States of America

⁷Center for Translational Immunology, Benaroya Research Institute, Seattle, United States of America

Find articles by Vandamme, N. in: PubMed | Google Scholar

¹Leuven Diabetes Lab, Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium

²VIB Laboratory of Translational Genetics, Leuven, Belgium

³Genomics Core Leuven, Centre for Human Genetics KU, Leuven, Belgium

⁴VIB Single Cell Core, Ghent, Belgium

⁵UCSF Diabetes Center, Immune Tolerance Network (ITN, San Francisco, United States of America

⁶Center for Systems Immunology, Benaroya Research Institute, Seattle, United States of America

⁷Center for Translational Immunology, Benaroya Research Institute, Seattle, United States of America

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

¹Leuven Diabetes Lab, Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium

²VIB Laboratory of Translational Genetics, Leuven, Belgium

³Genomics Core Leuven, Centre for Human Genetics KU, Leuven, Belgium

⁴VIB Single Cell Core, Ghent, Belgium

⁵UCSF Diabetes Center, Immune Tolerance Network (ITN, San Francisco, United States of America

⁶Center for Systems Immunology, Benaroya Research Institute, Seattle, United States of America

⁷Center for Translational Immunology, Benaroya Research Institute, Seattle, United States of America

Find articles by Linsley, P. in: PubMed | Google Scholar |

¹Leuven Diabetes Lab, Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium

²VIB Laboratory of Translational Genetics, Leuven, Belgium

³Genomics Core Leuven, Centre for Human Genetics KU, Leuven, Belgium

⁴VIB Single Cell Core, Ghent, Belgium

⁵UCSF Diabetes Center, Immune Tolerance Network (ITN, San Francisco, United States of America

⁶Center for Systems Immunology, Benaroya Research Institute, Seattle, United States of America

⁷Center for Translational Immunology, Benaroya Research Institute, Seattle, United States of America

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

¹Leuven Diabetes Lab, Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium

²VIB Laboratory of Translational Genetics, Leuven, Belgium

³Genomics Core Leuven, Centre for Human Genetics KU, Leuven, Belgium

⁴VIB Single Cell Core, Ghent, Belgium

⁵UCSF Diabetes Center, Immune Tolerance Network (ITN, San Francisco, United States of America

⁶Center for Systems Immunology, Benaroya Research Institute, Seattle, United States of America

⁷Center for Translational Immunology, Benaroya Research Institute, Seattle, United States of America

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

¹Leuven Diabetes Lab, Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium

²VIB Laboratory of Translational Genetics, Leuven, Belgium

³Genomics Core Leuven, Centre for Human Genetics KU, Leuven, Belgium

⁴VIB Single Cell Core, Ghent, Belgium

⁵UCSF Diabetes Center, Immune Tolerance Network (ITN, San Francisco, United States of America

⁶Center for Systems Immunology, Benaroya Research Institute, Seattle, United States of America

⁷Center for Translational Immunology, Benaroya Research Institute, Seattle, United States of America

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

J Clin Invest. https://doi.org/10.1172/JCI176403.
Copyright © 2025, Sassi 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 September 30, 2025 - Version history

Teplizumab, a humanized anti-CD3 monoclonal antibody, represents a breakthrough in autoimmune type 1 diabetes (T1D) treatment, by delaying clinical onset in stage 2 and slowing progression in early stage 3. However, therapeutic responses are heterogeneous. To better understand this variability, we applied single-cell transcriptomics to paired peripheral blood and pancreas samples from anti-mouse CD3-treated non-obese diabetic (NOD) mice and identified distinct gene signatures associated with therapy outcome, with consistent patterns across compartments. Success-associated signatures were enriched in NK/CD8⁺ T cells and other immune cell types, whereas resistance signatures were predominantly expressed by neutrophils. The immune communities underlying these response signatures were confirmed in human whole-blood sequencing data from the AbATE study at 6 months, which assessed teplizumab therapy in stage 3 T1D. Furthermore, baseline expression profiling in the human TN10 (stage 2) and AbATE (stage 3) cohorts identified immune signatures predictive of therapy response, T cell-enriched signatures in responders and neutrophil-enriched signatures in non-responders, highlighting the roles of both adaptive and innate immunity in determining teplizumab outcome. Using an elastic-net logistic regression model, we developed a 26-gene blood-based signature predicting teplizumab response (AUC = 0.97). These findings demonstrate the predictive potential of immune gene signatures and the value of transcriptomic profiling in guiding individualized treatment strategies with teplizumab in T1D.

Version 1 (September 30, 2025): In-Press Preview

Neutrophil-enriched gene signature correlates with teplizumab therapy resistance in different stages of type 1 diabetes

Gabriele Sassi,¹ Pierre Lemaitre,¹ Laia Fernández Calvo,¹ Francesca Lodi,² Álvaro Cortés Calabuig,³ Samal Bissenova,¹ Amber Wouters,¹ Laure Degroote,¹ Marijke Viaene,¹ Niels Vandamme,⁴ Lauren Higdon,⁵ Peter S. Linsley,⁶ S. Alice Long,⁷ Chantal Mathieu,¹ and Conny Gysemans¹

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Neutrophil-enriched gene signature correlates with teplizumab therapy resistance in different stages of type 1 diabetes

Gabriele Sassi,1 Pierre Lemaitre,1 Laia Fernández Calvo,1 Francesca Lodi,2 Álvaro Cortés Calabuig,3 Samal Bissenova,1 Amber Wouters,1 Laure Degroote,1 Marijke Viaene,1 Niels Vandamme,4 Lauren Higdon,5 Peter S. Linsley,6 S. Alice Long,7 Chantal Mathieu,1 and Conny Gysemans1

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Gabriele Sassi,¹ Pierre Lemaitre,¹ Laia Fernández Calvo,¹ Francesca Lodi,² Álvaro Cortés Calabuig,³ Samal Bissenova,¹ Amber Wouters,¹ Laure Degroote,¹ Marijke Viaene,¹ Niels Vandamme,⁴ Lauren Higdon,⁵ Peter S. Linsley,⁶ S. Alice Long,⁷ Chantal Mathieu,¹ and Conny Gysemans¹