Even in the absence of infection or inflammation, cDCs continuously undergo a hardwired process of homeostatic maturation, culminating in the CCR7-driven migration into the draining lymph node as migratory DCs (migDCs). This homeostatic maturation program overlaps with, yet is distinct from, pathogen-induced maturation. Most notably, rather than precipitating T cell activation, homeostatic DC maturation has been proposed to mediate peripheral tolerance via interactions between migDCs and regulatory T (Treg) cells. We previously identified Etv3, a transcriptional repressor of the ETS family, as a DC-specific, cell-intrinsic regulator of DC maturation and tolerogenic function in the steady state. Ongoing work in the lab endeavors to better characterize the transcriptional circuits that drive the “tolerogenic” vs “immunogenic” maturation of DCs.

As the key antigen-presenting cells of the immune system, DCs readily interact with T cells to drive particular immunological responses. In the steady state, migDCs have been shown to extensively co-localize with Treg cells. We have demonstrated that Etv3-deficient migDCs, in part through their aberrant upregulation of the costimulatory molecule OX40L, drove the expansion of dysfunctional CD25loFoxP3lo Treg cells, supporting a model wherein migDCs enforce peripheral tolerance via Treg cell maintenance. We are currently exploring how interactions between DCs, conventional T cells, and Treg cells, both in the steady state and during immune perturbations, shape the functional outcome of T cell responses.

Upon direct pathogen recognition, DCs induce an elaborate transcriptional and functional program within hours, suggesting that DC sentinel function may be pre-programmed during their development. Indeed, in two complementary studies, we have identified a key role for chromatin in the anticipatory control of DC sentinel function. In cDCs, the chromatin-organizing cohesin complex was required for optimal type 1 cDC differentiation, and subsequently their antigen cross-presentation, IL-12 secretion and antitumor function. In pDCs, several layers of chromatin regulation at the IFN-I locus was an essential, cell type-specific adaptation facilitating the unique IFN-I-producing capacity of pDCs. Our work aims to further dissect the transcriptional and epigenetic programs during DC development that poise mature DCs for their function.