Donor-derived CD8<sup>+</sup>CD122<sup>+</sup> Tregs generated in mixed donor chimeric NOD mice suppress autoreactive T cells

Shiva Pathak; Cameron S. Bader; Bettina P. Iliopoulou; Shobha Regmi; Pin-I Chen; Biki Gupta; Xiangni Wu; Blake Mosher; Alexandra Wells; Levon Witherspoon; Kayla C. Jenkins; William Harper; Emily Y. SooHoo; Abigail Twoy; Rizwan Ahmed; Suparna Dutt; Nadine Nagy; Kent P. Jensen; C. Garrison Fathman; Avnesh S. Thakor; Mark M. Davis; Everett H. Meyer

doi:10.1172/JCI207024

¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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¹Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, United States of America

²Department of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, United States of America

³Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, United States of America

⁴Department of Radiation Oncology, Stanford University School of Medicine, Stanford, United States of America

⁵Department of Radiology, Stanford University School of Medicine, Stanford, United States of America

⁶Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, United States of America

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J Clin Invest. https://doi.org/10.1172/JCI207024.
Copyright © 2026, Pathak 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 October 27, 2026 - Version history

The establishment of mixed hematopoietic chimerism is a promising way to induce immune tolerance for islet replacement therapy and to treat the underlying autoimmunity in type 1 diabetes (T1D). Mixed chimerism not only promotes effective thymic negative selection of autoreactive cells but also restores regulatory T cell (Treg) function and peripheral tolerance. In the current study, we determined that a novel class of donor-derived CD8⁺CD44⁺CD122⁺ Tregs (d-CD8⁺CD122⁺ Tregs) plays a crucial role in controlling autoimmunity in non-obese diabetic (NOD) mice with induced mixed chimerism. Using adoptive T cell transfer experiments, we showed that d-CD8⁺CD122⁺ Tregs abrogate autoimmunity by suppressing the exogenously injected diabetogenic T cells in Recombination-Activating Gene deficient NOD mice. These d-CD8⁺CD122⁺ Tregs from NOD chimeras show upregulation of Helios, Programmed cell death protein 1, perforin, granzyme-B, CD39, Folate receptor 4, and downregulation of proinflammatory marker SCART1. Using in vitro assays, we show that d-CD8⁺CD122⁺ Tregs respond specifically to a Complementarity-Determining Region-3 peptide sequence derived from T cell receptors of islet antigen-specific autoreactive T cells. Similarly, we found that individuals with T1D have a deficiency in CD8⁺CD122⁺ Tregs, suggesting a potential loss of regulatory function accompanies disease onset. Revitalizing CD8⁺CD122⁺ Tregs may offer a new therapeutic strategy of restoring immune tolerance in autoimmune diabetes.

Version 1 (October 27, 2026): In-Press Preview

Donor-derived CD8⁺CD122⁺ Tregs generated in mixed donor chimeric NOD mice suppress autoreactive T cells

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Donor-derived CD8⁺CD122⁺ Tregs generated in mixed donor chimeric NOD mice suppress autoreactive T cells