*Purpose: Lymphocyte activation gene-3 (LAG3) is a coinhibitory receptor on the surface of T and B lymphocytes, NK cells and plasmacytoid dendritic cells. Its functions in T cells are well studied, however its role in humoral immune responses remains poorly characterized and there have been few studies on the role of LAG3 in transplantation.The goal of this study was to test the role of recipient LAG3 in a mouse model of renal allograft rejection

*Methods:

*Results: Compared to WT animals, naïve B6.LAG3^-/-mice exhibit a modest increase in splenic cellularity with T cell pool skewed toward central and effector memory cells and have increased numbers of both foxp3- and foxp3⁺CXCR5^hi follicular T cells. The numbers of B220⁺CD138⁺plasma cells were significantly increased in the spleen of LAG3 deficient mice whereas other B cell subsets were not altered. Despite this phenotype LAG3^-/-mice do not develop spontaneous autoimmunity without antigen challenge.IFNγELISPOT assay demonstrated that naïve B6.LAG3^-/-(H-2D^b) mice have increased frequencies of preexisting memory T cells reactive against BALB/c (H-2D^d), SJL (H-2D^s), DBA (H-2D^q) and C3H (H-2D^k) alloantigens. C3H kidney allografts were transplanted into B6.WT or B6.LAG3^-/-recipients after bilateral nephrectomy. Whereas 4 out of 4 WT recipients accepted C3H allografts for longer than 60 d, recipient LAG3 deficiency led to rapid allograft rejection (MST of 14 d, n=5) with serum creatinine levels of 0.1 and 1.35 mg/dl respectively at d14 posttransplant (<0.4 mg/dl in non-transplanted mice).

Graft histology at d14 demonstrated decreased T cell infiltration in LAG3^-/-vs WT recipients. However, we observed diffuse intragraft C4d staining, atrophic peritubular capillaries, endothelial swelling and edema characteristic of antibody mediated rejection. Compared to WT, LAG3^-/-recipients had elevated frequencies of anti-donor IFNγproducing T cells measured by ELISPOT and increased levels of donor MHC-II (I-A^k) specific antibodies measured by ELISA at 14d posttransplant. Depleting recipient CD8 T cells did not alter the rejection kinetics in LAG3^-/- recipients (MST of 16 d). In contrast, B cell depletion significantly extended C3H kidney allograft survival (MST of >100 d).

*Conclusions: Taken together, these results suggest the predominant role of alloantibody rather than T cells in renal allograft injury and identify LAG3 is a potential therapeutic target for the prevention and treatment of antibody mediated rejection.

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