Abstract 14475: Intrinsic T Cell Tolerance to the Autoantigen LL-37 is Mediated in Part by Platelets

Circulation, Volume 148, Issue Suppl_1, Page A14475-A14475, November 6, 2023. Introduction:An autoimmune response to human cathelicidin antimicrobial peptide LL-37, a component of neutrophil extracellular traps (NETs), may play a role in athero-thrombosis. We have reported that acute coronary syndrome (ACS) patients have increased LL-37 auto-reactive CD8+CD69+CD137+ T cells compared to healthy controls suggesting breach of tolerance to LL-37. Platelets present antigens to CD8+ T cells via HLA Class-I but it is unknown if this pathway is involved in maintaining intrinsic tolerance to the autoantigen LL-37. In this study, we investigated the role of platelets in maintaining immune tolerance to LL-37 in healthy subjects.Methods and Results:Platelets and autologous peripheral blood mononuclear cells (PBMCs) were isolated from remnant blood of platelet donor Leukocyte Reduction System cones from the institutional blood bank. Platelet enrichment was confirmed by CD41+ flow cytometry and over 95% were HLA Class-I(+). PBMCs were co-cultured with autologous platelets that were either non-primed or primed with LL-37 peptide at a ratio of 25:1 platelet-to-PBMC. Cells were collected after 16 hours and subjected to fluorescent staining for activation markers by flow cytometry. Compared to non-primed platelets, co-culture of LL-37-primed platelets significantly reduced T cell activation in autologous PBMCs including CD8+CD69+CD137+ T cells, CD4+CD134+ T cells and CD4+CD134+CD137+ T cells (Table), supporting platelet-mediated T cell tolerance to LL-37. We then evaluate if the breach in T cell tolerance to LL-37 in ACS is related to platelet counts. CD8+CD69+CD137+ T cell response to LL-37 in PBMCs of ACS patients was negatively correlated with platelet count (N=21; Pearson r = -0.438, P=0.047).Conclusions:The results demonstrate that intrinsic immune tolerance to the autoantigen LL-37 in healthy subjects is mediated in part by platelets. Reduced platelet counts are implicated in the breach of immune tolerance to LL-37 in ACS.

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Novembre 2023