Fibrinogen-like protein 1 prevents antibody production in a LAG3 dependent manner 3502

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Abstract Description Coinhibitory receptor Lymphocyte Activation Gene 3 (LAG3) is expressed on a wide range of immune cells. We have established that LAG3 deficient kidney transplant recipients, acutely reject their kidney allografts via antibody mediated rejection. Based on this, we hypothesized that stimulation of LAG3 would diminish antibody production. To test whether LAG3 agonism could diminish antibody responses we performed plasma cell ELISPOT assays and crosslinked LAG3 with primary and secondary antibodies or with LAG3 ligand Fibrinogen-like protein 1 (FGL1), resulting in decreased IgG production by plasma cells. Furthermore, use of conditional knockout mice indicated this was plasma cell intrinsic. We next tested our hypothesis in an immunization model. Mice immunized with NP-KLH and treated with FGL1 had decreased anti-NP antibodies compared to untreated immunized mice. Finally, we tested the ability of LAG3 to regulate antibody responses in a model of antibody mediated rejection in kidney transplantation. Untreated mice acutely reject their kidney grafts (MST = 7d), while LAG3 agonism via FGL1 treatment significantly prolonged graft survival with 66% of recipients surviving beyond day 80. Together these findings demonstrate that LAG3 is a mediator of humoral immune responses, with therapeutic potential in transplantation. Funding Sources Supported by the Cleveland Clinic Global Center for Pathogen & Human Health Young Investigator Award Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

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