The goal of this project is to unveil how the immune-privileged central nervous system (CNS) initiates immune-surveillance during viral infection. In the healthy state, the CNS is separated from the immune system by the blood brain barrier. When the CNS encounters viral invasion, immune cells enter the CNS to clear viral infection; meanwhile, regulation must exist to prevent excessive immune response from causing auto-immune disorder. In the immune system outside the CNS, such regulation depends on regulatory T cells (Tregs). Tregs not only facilitate homing of immunocytes for clearance of infection, but also suppress self-reactive T cels thereby minimizing autoimmunity. Tregs have been shown to accumulate in the CNS during viral infection. However, the steady state CNS is devoid of T cells. Therefore, what directs Treg entry into the CNS during infection remains a key question in the field of CNS anti-viral immunity. Our preliminary studies indicate that Treg entry into the infected CNS appears to be regulated by a population of DCs in the meninges, which we recently identified. Our data show that these meningeal DCs derive from bone marrow precursors during infection, and suggest that type I interferon (IFN) and an IFN-induced transcription co-factor p204, may be responsible for driving a transition from precursors to meningeal DCs. We posit that the meningeal DC, an efficient antigen-presenting cell, is the gate-keeper for T cell entry into the CNS. In this model, meningeal DCs are essential for detecting infection and mediating Treg entry during CNS infection. We will test this hypothesis by using unique techniques established in my laboratory and various animal models at our disposal, to address 1) how meningeal DCs develop and respond to infection; and 2) what the role of meningeal DCs play in recruitment of Treg into the CNS. In summary, the studies in this proposal will demonstrate how the innate DCs at the meninges orchestrate CNS immunity by recruiting Tregs at the gates during viral infection. This will lay the groundwork for a novel therapeutic strategy directing the CNS immune response by targeting precursor to meningeal DCs.
Dysfunctional immune responses in the central nervous system (CNS) cause diseases related to CNS infection and inflammation. Understanding the cellular and molecular mechanisms underlying CNS immunity during viral infection is of great medical interest. Here, we will unveil how meningeal dendritic cells orchestrate immune response in the infected CNS, as such providing an attractive therapeutic target for directing CNS anti- viral immunity. !
|Lee, Jaeyop; Zhou, Yu Jerry; Ma, Wenji et al. (2017) Lineage specification of human dendritic cells is marked by IRF8 expression in hematopoietic stem cells and multipotent progenitors. Nat Immunol 18:877-888|
|Lee, Jaeyop; Breton, Gaëlle; Oliveira, Thiago Yukio Kikuchi et al. (2015) Restricted dendritic cell and monocyte progenitors in human cord blood and bone marrow. J Exp Med 212:385-99|
|Lee, Jaeyop; Breton, Gaëlle; Aljoufi, Arafat et al. (2015) Clonal analysis of human dendritic cell progenitor using a stromal cell culture. J Immunol Methods 425:21-26|
|Puhr, Sarah; Lee, Jaeyop; Zvezdova, Ekaterina et al. (2015) Dendritic cell development-History, advances, and open questions. Semin Immunol 27:388-96|
|Breton, Gaëlle; Lee, Jaeyop; Zhou, Yu Jerry et al. (2015) Circulating precursors of human CD1c+ and CD141+ dendritic cells. J Exp Med 212:401-13|
|Breton, Gaëlle; Lee, Jaeyop; Liu, Kang et al. (2015) Defining human dendritic cell progenitors by multiparametric flow cytometry. Nat Protoc 10:1407-22|
|Ghosh, Hiyaa S; Ceribelli, Michele; Matos, Ines et al. (2014) ETO family protein Mtg16 regulates the balance of dendritic cell subsets by repressing Id2. J Exp Med 211:1623-35|
|Franklin, Ruth A; Liao, Will; Sarkar, Abira et al. (2014) The cellular and molecular origin of tumor-associated macrophages. Science 344:921-5|
|Subramanian, Manikandan; Hayes, Crystal D; Thome, Joseph J et al. (2014) An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo. J Clin Invest 124:1296-308|