ItpkB regulates CCR7 expression on dendritic cells prior to lymph node trafficking

Abstract

Abstract Dendritic cells (DC) are fundamental in the initiation of the adaptive immune response. Following antigen uptake, tissue-resident DCs undergo maturation in preparation for their migration to lymph nodes where they present processed antigen to T cells. Down-regulation of tissue-homing receptors and upregulation of lymphoid-homing receptors, including CCR7 is required for dendritic cell entry into afferent lymphatic vessels. CCR7 binding to its ligands, CCL19 and CCL21, provides the appropriate directional cues for DCs to traffic to lymph nodes. Although both maturation and migration of DCs have been extensively studied, it still remains unclear what signaling pathways are responsible for inducing CCR7 expression. We found that DCs deficient in inositol-trisphosphate 3-kinase B (ItpkB) express higher levels of CCR7. ItpkB-deficient BMDCs migrate to draining lymph nodes more efficiently in both competitive and noncompetitive environments compared to their wild-type counterparts. We have previously shown that ItpkB deficiency leads to enhanced Akt activation in NK cells. Western blot analysis showed that ItpkB-deficiency in DCs also leads to increased basal and LPS-induced Akt1 activation. To determine whether hyper-Akt activity is sufficient to trigger enhanced lymph node homing, we expressed two forms of constitutively active Akt1, Myr-Akt1 and Akt1 T308E, S473D, in wildtype DCs. Akt1 hyperactivity was sufficient to promote CCR7 expression but did not affect DC maturation. Our findings suggest that ItpkB regulates CCR7 expression on dendritic cells as they prepare to traffic to draining lymph nodes for the purpose of primary T cell responses.