Molecular Basis of cDC1 Development

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ABSTRACT The initial adaptive immune response to tumors and many viruses relies on the priming of CD8 T cells to gen- erate cytolytic effector T cells that can specifically target tumors or virally infected cells. The priming of CD8 T cells to these agents is carried out in vivo by a particular type of antigen presenting cell that is a component of the myeloid system and a member of the family of dendritic cells. Classical dendritic cells (cDCs) comprise several closely related lineages that are clearly distinct from other myeloid cells such as macrophages, mono- cytes or granulocytes. Primarily, cDCs serve to activate T cells against infections in the central lymphoid tis- sues, rather than carrying out direct effector functions at sites of infections as the other myeloid lineages do. The cDCs are themselves comprised of at least two major branches, now called cDC1 and cDC2. The cDC1 is a lineage that specializes in the uptake and processing of cell-associated antigens, such as from tumors of virally infected cells and the expression of peptide epitopes on its cell surface in conjunction with MHC-I mole- cules. This form of antigen:MHC-I complex is able to activate CD8 T cells, and not CD4 T cells. This process is called cross-presentation. The cDC2 is not capable of carrying out cross-presentation to viruses or tumors in vivo. The cDC1 has many genetic and molecular differences from cDC2; cDC1 require a distinct set of tran- scription factors for their development that are not required for cDC2. This includes dependence on the tran- scription factors Nfil3, Id2, Irf8 and Batf3. Our recent work showed that the genetic hierarchy among these fac- tors has Nfil3 as the first and initiating factor, acting to indirectly induce Id2 and Batf3 via the suppression of the repressor Zeb2. However, it is still unknown how Nfil3 is induced to initiate this process, and how Nfil3 works to suppress Zeb2 expression. It has recently become important to understand these details because of the clini- cal interest to apply Flt3L administration as a therapeutic in expanding the in vivo population of cDC1. It has been known for some time that Fl3L can expand dendritic cells in general and expand cDC1 in particular. But we have uncovered a surprising and worrisome fact; Flt3L administration will expand cDC1-like cells even in Nfil3-deficient mice, which completely lack cDC1 beforehand. The expansion of cDC1 in Nfil3-deficent mice produced by Flt3L is of the same magnitude as the expansion in WT mice. Thus, Flt3L is inducing cDC1 by a different genetic route than normal cDC1 development. There has been no test of whether such cDC1 cells function normally and will boost an immune response. This application will systematically address this issue by Aim 1) defining the normal process by which Nfil3 is induced, Aim 2) define the mechanism by which NFIL3 drives cDC1 development, and Aim 3) determine whether Flt3-induced cDC1 function normally and determine the mechanism by which Flt3L bypasses the normal requirement for Nfil3 in cDC1 development.