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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