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LAG-3 Deletion Upregulates Memory in a Dendritic Cell-Dependent Process

S. Gibney,1 M. Efre,1 T. Ashry,1 C. Yang,1 T. O'Shea,1,2 R. White,2 P. Russell,1 J. Madsen,1 R. Colvin,2 A. Alessandrini.1,2

1Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA
2Department of Pathology, Massachusetts General Hospital, Boston, MA.

Meeting: 2018 American Transplant Congress

Abstract number: A407

Keywords: Allorecognition, Skin transplantation, T cells, Tolerance

Session Information

Session Name: Poster Session A: Tolerance / Immune Deviation

Session Type: Poster Session

Date: Saturday, June 2, 2018

Session Time: 5:30pm-7:30pm

 Presentation Time: 5:30pm-7:30pm

Location: Hall 4EF

Introduction. Cardiac transplantation is critical for management of severe heart failure, but cardiac allografts frequently undergo chronic T-cell-mediated allograft rejection. Our research demonstrates that Lymphocyte Activation Gene-3 (LAG-3), a transmembrane and solubilized protein, is necessary for recipient dendritic cells to inhibit generation of allograft-specific T-cell memory.

Methods. Allogeneic mouse strains were used as cardiac and skin allograft donors and recipients. DBA/2 cardiac or skin allografts were transplanted without immunosuppression into wild type B6 controls and LAG-3-/- B6 knockout mice. At serial time points after transplantation, recipient spleens were harvested and pan-T cell IFN-g response to donor antigen, a marker of memory, was assessed via ELISPOT. In a second set of experiments, skin transplants were repeated with 8 and 19 week old mice. Before grafting, recipients were injected with bone marrow and splenic LAG-3+ dendritic cells or LAG-3+ splenic T cells.

Results. Cardiac and skin allografts in WT recipients exhibited slower rejection times by 2-4 days than LAG-3 KO recipients. A greater number of IFN-g secreting cells were observed among LAG-3 KO T cells at 1, 2, and 5 weeks after heart transplant rejection and at 3, 4, and 5 weeks after skin transplant rejection. The increased number of IFN-g secreting LAG-3-/- T cells relative to LAG-3 WT T cells across all time points was statistically significant for cardiac allograft recipients (p=0.003**) and skin allograft recipients (p=0.006**). The enhanced memory response in LAG-3 KO recipients was not observed with 19-week-old recipients when compared to 8 week-old recipients.

Adoptive transfer of purified LAG-3+ dendritic cells into 8-week-old LAG-3 KO recipients one week prior to skin allografts resulted in a IFN-g response to donor antigen similar to WT recipients when compared to untreated LAG-3 KO recipients.

Conclusion. Our research suggests that dendritic cells are important for controlling T-cell memory generation. Adoptive transfer of LAG-3+ dendritic cells, but not LAG-3+ T cells, reduced memory T-cell reactivity to that of wild-type recipients in LAG-3 KO recipients. This suggests that LAG-3+ dendritic cells may help minimize chronic antigen presentation.

CITATION INFORMATION: Gibney S., Efre M., Ashry T., Yang C., O'Shea T., White R., Russell P., Madsen J., Colvin R., Alessandrini A. LAG-3 Deletion Upregulates Memory in a Dendritic Cell-Dependent Process Am J Transplant. 2017;17 (suppl 3).

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To cite this abstract in AMA style:

Gibney S, Efre M, Ashry T, Yang C, O'Shea T, White R, Russell P, Madsen J, Colvin R, Alessandrini A. LAG-3 Deletion Upregulates Memory in a Dendritic Cell-Dependent Process [abstract]. https://atcmeetingabstracts.com/abstract/lag-3-deletion-upregulates-memory-in-a-dendritic-cell-dependent-process/. Accessed June 6, 2025.

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