Recipient LAG3 deficiency results in antibody-mediated rejection of mouse renal allografts

Abstract

Abstract The functions of coinhibitory receptor lymphocyte activation gene-3 (LAG3) in T cells are 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 rejection Compared to WT animals, naïve B6.LAG3−/− mice have increased splenic cellularity and higher frequencies of CD44hi memory T cells, CXCR5hi follicular T cells, and B220+CD138+plasma cells yet do not develop spontaneous autoimmunity. Furthermore, naïve B6.LAG3−/−(H-2Db) mice have increased frequencies of memory T cells against H-2Dd, H-2Ds, H-2Dq and H-2Dk alloantigens. C3H (H-2Dk) kidney allografts were transplanted into B6.WT or B6.LAG3−/− recipients after bilateral nephrectomy. Whereas 4/4 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. 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 IFNg producing T cells and increased levels of anti-donor MHC-II antibodies. Recipient CD8 T cell depletion did not alter the rejection kinetics in LAG3−/− recipients (MST of 16 d), while B cell depletion significantly extended C3H kidney allograft survival (MST of >30 d). 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 AMR prevention and treatment.