AIF1 expression regulates differentiation of dendritic cells from hematopoietic stem cell multipotent progenitor subsets and regulates antigen presentation capacity

Abstract

Abstract Dendritic cells (DC) are indispensable in orchestrating adaptive immunity, serving as the principal messengers between innate and adaptive arms. DC subsets are derived from CD34+ hematopoietic stem cells (HSC). DC development progress through differentiation from HSC multipotent progenitors towards common myeloid progenitors. However, additional proteins involved in this selective differentiation process remain to be identified. For these studies, use of transcriptomic profiling and RNA interference (RNAi) approaches have now identified that Allograft Inflammatory Factor-1 (AIF1) directly contributes to DC differentiation and immunomodulatory processes. HSC multipotent progenitors, identified as CD117+Lin-CD34+SCA1+, were found to not express AIF1. However, CD117+Lin-CD34+SCA1- and CD117+Lin-CD34-SCA1- subsets, known as the oligopotent progenitors, did express AIF1. Importantly, this was restricted to common myeloid progenitors, as the common lymphoid progenitors, defined as CD117+Lin-SCA1-IL-7Rα+ did not express AIF1. RNAi knockdown of AIF1 in sorted Lin-CD34−CD117+SCA1+ cells led to restrained differentiation in DC upon culturing with GM-CSF. Interestingly, knockdown of AIF1 in committed CD11c+ DC resulted in impaired antigen presentation to cognate CD4+ T cells in vitro, suggesting an important immunostimulatory role in committed myeloid lineages. Current studies are now adoptively transferring HSC knocked out for AIF1 into mice to assess in vivo DC differentiation ability and capacity to migrate and populate the splenic compartment. This is the first report showing the novel role of AIF1 in dendritic cell development and antigen presentation.