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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Alloimmunity and Transplantation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1516772

Pre-Transplant T-Cell Clonal Analysis Identifies CD8 + Donor Reactive Clones that Contribute to Kidney Transplant Rejection

Provisionally accepted
Jes M Sanders Jes M Sanders 1Barbara L Banbury Barbara L Banbury 2Erika L Schumacher Erika L Schumacher 2Jie He Jie He 1Yuvaraj Sambandam Yuvaraj Sambandam 1Paul A Fields Paul A Fields 2Lorenzo Gallon Lorenzo Gallon 3,4James M Mathew James M Mathew 1,4,5*Joseph R Leventhal Joseph R Leventhal 1,4
  • 1 Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, United States
  • 2 Adaptive Biotechnologies (United States), Seattle, Washington, United States
  • 3 Department of Medicine, Division of Nephrology Northwestern University, Feinberg School of Medicine, Chicago, IL, United States
  • 4 Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, Illinois, United States
  • 5 Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States

The final, formatted version of the article will be published soon.

    Introduction: Responses to allogeneic human leukocyte antigen (HLA) molecules limit the survival of transplanted organs. The changes in T-cell alloreactivity that contribute to this process, however, are not fully understood. We defined a set of donor reactive T-cell clones (DRTC) with the goal to elucidate signatures of kidney allograft rejection. Methods: DRTC were identified pretransplant using an anti-donor mixed lymphocyte reaction assay: CFSE-diluting CD4 + and CD8 + DRTC were flow-sorted, and the TCR sequences were identified using Adaptive Immunosequencing. DRTC were then tracked in post-transplant biopsies, blood, and urine samples in a cohort of kidney transplant recipients. Results: In patients with an abnormal biopsy, the majority of CD8 + DRTC found within the allograft were detected in the circulating pre-transplant repertoire. Circulating CD8 + DRTC were more abundant pre-and post-transplant in patients that received non-lymphodepletional induction and developed an abnormal biopsy when compared to stable patients. Additionally, DRTC were detected as early as two weeks post-transplant in the urine of some patients, with some of these clones subsequently identified in follow-up kidney biopsy samples. Discussion: The findings of our study add to our understanding of T-cell alloreactivity following kidney transplantation and provide evidence for the role of pre-defined alloreactive T-cells in the development of allograft rejection.

    Keywords: Kidney transplant rejection1, alloreactivity2, T-cell receptor sequencing3, T-cell mediated rejection4, Mechanisms of rejection5

    Received: 24 Oct 2024; Accepted: 02 Jan 2025.

    Copyright: © 2025 Sanders, Banbury, Schumacher, He, Sambandam, Fields, Gallon, Mathew and Leventhal. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: James M Mathew, Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.