Interleukin-6 receptor α signaling on CD4+ T cells drives RBC alloantibody generation and T follicular helper cell differentiation in a murine model of RBC alloimmunization.

Abstract

Abstract Alloimmunization to non-ABO red blood cell (RBC) antigens remains a significant clinical problem in transfusion medicine. Presence of these alloantibodies can lead to delayed hemolytic transfusion reactions resulting in significant morbidity and occasional mortality upon antigenic re-exposure. For patients that generate multiple alloantibodies, provision of compatible antigen-negative RBCs can be time and resource intensive. In rare cases, it can result in the inability to locate and provide a life-saving therapy. Despite the significant clinical consequences of RBC alloimmunization, our understanding of the fundamental molecular and cellular mechanisms regulating anti-RBC antibody generation is limited. We have combined a recently developed mouse model for transfusion mediated RBC alloimmunization with mice genetically deficient in interleukin-6 receptor (IL-6Rα) to investigate the role of IL-6Rα signaling in regulating RBC alloimmunization. We have demonstrated that IL-6Rα signaling plays a key role in the generation of anti-RBC alloantibodies in response to transfused RBCs. Additionally, we have shown that RBC alloimmunization requires IL-6Rα signaling specifically on T cells, and that these signals are required for maximal in vivo differentiation of naïve anti-RBC specific CD4+ T cells into T follicular helper (TFH) cells. We have identified for the first time a specific molecule (IL-6Rα), its downstream cellular target (CD4+ T cells) and resultant functional outcome (TFH differentiation) that regulates RBC alloimmunization. Collectively, our findings support the idea that currently available biologics targeting IL-6Rα could be a viable therapeutic option for the prevention of RBC alloimmunization.