Human Dendritic Cell Heterogeneity: Opportunities and Challenges for the Control of Immunity

Abstract

Abstract SCI-21Dendritic cells (DCs) comprise a heterogeneous population of potent antigen-presenting cells, which are master orchestrators of the immune response. DCs initiate immunity, and just as importantly, control its quality and outcome. DCs accomplish this by capitalizing on their defined subsets, which exert discrete functions in responding to different types of antigens and factors in the microenvironment. DCs, therefore, provide the immune system with an essential and robust flexibility to discriminate between enormous numbers of harmful and benign agents and to mount functionally distinct and appropriate responses in the contexts of innate and adaptive immunity. Our lab has focused on the contrasting functions of conventional human DC subsets, primarily monocyte-derived DCs (moDCs) versus CD34+ hematopoietic progenitor cell-derived Langerhans-type DCs (LCs). Recent findings that have defined the afferent sensitization of different types of immune responses by these distinct DC subtypes will be discussed. For example, LCs use an endogenous IL-15R-α/IL-15 mechanism to generate potent cytotoxic T lymphocytes and break tolerance against a self-differentiation tumor antigen like WT1. This contrasts with the potency of moDCs in maturing and stimulating NK cells by their production of IL-12p70, whereas LCs can only ensure NK-cell viability. The application of these findings to the holy grail of separating graft-versus-leukemia from the deleterious aspects of graft-versus-host disease in allotransplantation, at the level of afferent sensitization by these distinct DC subtypes, as well as the novel use of small-molecule inhibitors of JAK-STAT signaling in DC-stimulated T cells, will also be addressed. Disclosures:Off Label Use: JAK2 inhibitors (potentially several) for inhibition of dendritic cell stimulated alloreactivity - but all data will be in vitro, so perhaps this is not off-label drug use because it is not in vivo in humans.