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PD-1 Expression on CD8+ T Cells Contributes to the Establishment of Mixed Chimerism-Based Operational Tolerance

C. J. Little, S. C. Kim, J. Fechner, J. Post, M. Winslow, D. B. Kaufman

Surgery, University of Wisconsin, Madison, WI

Meeting: 2022 American Transplant Congress

Abstract number: 1286

Keywords: Kidney transplantation, Primates, T cells, Tolerance

Topic: Basic Science » Basic Science » 12 - Immunosuppression & Tolerance: Preclinical & Translational Studies

Session Information

Session Name: Immunosuppression & Tolerance: Preclinical & Translational Studies

Session Type: Poster Abstract

Date: Monday, June 6, 2022

Session Time: 7:00pm-8:00pm

 Presentation Time: 7:00pm-8:00pm

Location: Hynes Halls C & D

*Purpose: PD-1 is a T cell co-inhibitory molecule involved in T cell exhaustion and antigen specific hypo-reactivity. Given the role of PD-1 signaling in the development of self-tolerance and tumor immune evasion, we sought to elucidate its contribution to engraftment of donor hematopoietic cells (HCs) and establishment of mixed chimerism-based operational tolerance in a nonhuman primate model.

*Methods: As shown in Figure 1A, a non-myeloablative, helical tomotherapy-based total lymphoid irradiation, ATG, and Belatacept conditioning regimen was applied to a 3-5 MHC antigen mismatched rhesus macaque kidney + HC transplant model. The maintenance immunosuppression regimen included MMF, sirolimus, and tacrolimus tapers. The experimental cohort consisted of 8 animals. Flow cytometry was utilized for cellular immunophenotyping and PD-1 analysis. Mixed lymphocyte reactions (MLRs) were performed in the presence of a monoclonal anti-PD-1 blocking agent for in vitro functional assessment.

*Results: Mixed chimerism was achieved in 37.5% (3/8) of recipients. None of the chimeric animals developed evidence of alloreactivity. In contrast, 4 of 5 non-chimeric macaques succumbed to antibody- and cellular-mediated rejection. There was an upregulation of PD-1 expression on the surface of emerging host CD8+ T cells in chimeric animals, represented by a 4-fold increase in percentage of PD-1hi cells compared to non-chimeric recipients at 30 days post-infusion (Figure 1B; P=0.01). This effect was driven by a 4.5-fold differential of PD-1hi expression among CD8+ T effector memory cells, which was not observed in the central memory or naive subsets (Figure 1C; P=0.02). Importantly, CD8+ T cells were the predominant phenotype among the recovering immune system in both groups (P=0.001). Conversely the CD4+ phenotype, which represented the minority of circulating T cells, exhibited a similar relative frequency of PD-1hi expression irrespective of chimerism (Figure 1B). Furthermore, a 46% reduction in CD8+ PD-1hi expression was observed during episodes of acute rejection in the non-chimeric cohort (P=0.01). These findings coincided with in vitro studies utilizing PD-1 blockade in a post-induction allogenic MLR, which yielded a 3-fold increase in CD8+ T cell proliferation and gamma interferon production compared to non-blockade controls.

*Conclusions: PD-1 expression by CD8+ T cells plays an important role in controlling alloreactivity during engraftment of HCs and homeostatic recovery, thus contributing to the development of mixed-chimerism based operational tolerance.

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To cite this abstract in AMA style:

Little CJ, Kim SC, Fechner J, Post J, Winslow M, Kaufman DB. PD-1 Expression on CD8+ T Cells Contributes to the Establishment of Mixed Chimerism-Based Operational Tolerance [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/pd-1-expression-on-cd8-t-cells-contributes-to-the-establishment-of-mixed-chimerism-based-operational-tolerance/. Accessed May 16, 2025.

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