The Role of LAG3 in Antibody Responses To Kidney Transplantation

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Abstract The role of lymphocyte activation gene-3 (LAG3) in T cell functions is well studied, however its role in humoral immune responses remains poorly characterized. The goal of this study was to test the role of recipient LAG3 in a mouse model of renal allograft rejectionNaive B6.LAG3−/− mice have elevated numbers of follicular and memory T cells, and plasma cells compared to WT mice, as well as increased frequencies of memory T cells reactive to H-2Dd, H-2Ds, H-2Dq and H-2Dk alloantigens. When kidneys were transplanted from C3H donors to B6 WT and LAG3−/− mice, all C3H kidney allografts survived for > 60d in WT recipients, whereas LAG3−/− recipients rapidly reject allografts and have elevated serum creatinine levels at d14 posttransplant. Graft histology at rejection revealed minimal T cell infiltration, diffuse C4d staining, atrophic peritubular capillaries, endothelial swelling and edema characteristic of antibody mediated rejection (AMR). Compared to WT, LAG3−/− recipients had elevated frequencies of anti-donor IFNγ producing T cells and increased levels of donor specific antibody (DSA) against MHC-I and MHC-II. Depletion of CD8 T cells in LAG3−/− recipients did not alter rejection kinetics, while B cell depletion significantly extended C3H kidney allograft survival, suggesting the predominant role of alloantibody rather than T cell mediated rejection in these mice. However, neither T nor B cell conditional knockout recipients rejected the allograft demonstrating LAG3 expression on both cell types is necessary to mediate rejection. These findings demonstrate that LAG3 regulates both T and B cell functions in response to kidney allografts, and is an attractive therapeutic target for the prevention of AMR. Supported by grants from NIH (P01AI087586-10)

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