Cooperation between Retinoic Acid and Lymphotoxin Signals maintains Type 2 conventional dendritic cell homeostasis.

Dendritic cells (DC) are specialized antigen presenting cells that react to environmental cues to shape the immune response. As orchestraters of inflammatory or regulatory immune responses, DCs are precisely positioned at barrier sites where they act as the first line of defense against foreign antigens. Multiple DC subsets have been described in the immune system, each exhibiting unique functions and distinct ontogeny. Within the conventional DC (cDC) population, Type II conventional dendritic cells (cDC2) play a crucial role in initiating helper T cell responses and directing their differentiation into effector lineages. Recent studies have identified two distinct cDC2 subsets in lymphoid tissues; however, the cell-intrinsic and -extrinsic signals that shape cDC2 heterogeneity in peripheral and mucosal lymphoid tissues remain unclear. Herein we found that in the murine spleen and gut-associated lymphoid tissues (GALT), T-bet expressing cDC2s (termed cDC2a) intrinsically require retinoic acid receptor (RAR) signaling for their maintenance during the steady-state. While cDC2a in the GALT possess enzymatic machinery to metabolize RA from retinol, splenic cDC2a do not have this capacity. Our lab and others have previously shown the absence of DC-intrinsic lymphotoxin beta receptor (LTR) signaling results in a partial loss of cDC2 in the spleen. Using genetic and bone marrow chimera approaches, I determined that the previously described LTR-dependent cDC2 correspond to the cDC2a subset. However, unlike RAR signaling which was required to maintain T-bet expression in cDC2a, cDC2-intrinsic LTR signaling operated prior to the acquisition of T-bet to achieve optimal numbers of splenic cDC2a. Additionally, within the splenic marginal zone bridging channel, cDC2a preferentially accessed the blood and uniquely express retinol binding protein receptor 2 (RBPR2), a receptor for blood-derived retinol. In the absence of cDC2-intrinsic LTR, splenic cDC2s proliferated normally but were found to be more “restless”, exhibiting higher levels of F-actin content and a loss of preferential cDC2a blood access. Taken together, we propose a novel mechanism for cDC2a development in the spleen whereby cDC2-intrinsic LTR signaling limits F-actin accumulation to facilitate access to blood-borne retinol which in turn enables cDCa differentiation via RAR signaling.

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