Defining the Primary Immune Cell in the Immune Response to Coagulation Factor VIII 2245246

Abstract

Hemophilia A is an X-linked bleeding disorder caused by mutations in the F8 gene, leading to a deficiency of coagulation factor VIII (FVIII). However, FVIII infusions for the treatment of bleeding triggers the development of neutralizing FVIII antibodies in about 30% of patients with severe hemophilia A, rendering FVIII replacement therapy ineffective. Although several studies have demonstrated that various immune cells, such conventional dendritic cells (cDCs), macrophages, monocytes, and marginal zone B cells, co-localize or interact with FVIII, the primary immune cell population mediating FVIII immune recognition remains poorly explored. DCs endocytose and process FVIII into peptides, which are then recognized by CD4+ T cells that activate B cells to produce anti-FVIII antibodies. We hypothesize that type 2 cDCs (cDC2) mediate FVIII recognition and CD4+ T cell activation that enhances FVIII immunity. Batf3⁻/⁻ mice (cDC1 knockout [KO]), Zeb2-Delta3⁻/⁻ mice (cDC2 KO), and Zbtb46-DTR mice without diphtheria toxin depletion (WT) were utilized to isolate bone marrow-derived dendritic cells (BMDC). Immature BMDC endocytosed more FVIII than mature and intermediate-mature BMDC as expected. However, immature BMDC from cDC2 KO mice exhibited reduced FVIII uptake compared to those from WT and cDC1 KO mice. Although BMDC from cDC2 KO mice enhanced CD4+ T cell proliferation compared to WT mice, cDC2 KO mice treated with FVIII exhibited reduced anti-FVIII antibodies than WT mice. Together, these data suggest that cDC2 predominantly contributes to FVIII-specific adaptive immunity through FVIII uptake and promotion of CD4+ T cell proliferation. K99 Immune Mechanisms of Human Disease (HUM)