Function of ACKR3 in immune cell trafficking in lymphoid organs
In mammalians the efficiency of immune system mainly depends on leukocyte trafficking which in turn is largely regulated by locally confined chemokine patterns. Chemokines bind to cognate chemokine receptors expressed on defined leukocyte subsets mediating their directional migration. Atypical chemokine receptors (ACKRs) which do not stimulate cell migration, emerged recently as important regulators of chemokine availability and are instrumental for the shaping and maintenance of chemokine gradients. The current proposal further dwells on the function of the atypical receptor ACKR3 in secondary lymphoid organs (SLOs). Based on recent results from the laboratory, three distinct expression sites of the receptor will be investigated: the prominent expression of AKR3 on spleen sinusoids in the red pulp, the expression on a subset of marginal zone B cells (MZBs) and the presence on follicular dendritic cells (FDCs) in B cell follicles of SLOs. So far the described activity of ACKR3 is scavenging of the chemokine CXCL12 and, to a lesser extent, of CXCL11. We recently reported a recombinant chimeric chemokine that selectively interacts with ACKR3 and can be used to determine its scavenging activity in vivo and in vitro. The pronounced expression and efficient scavenging activity of the chimeric chemokine by ACKR3 on sinusoids in spleen, suggest that depletion of CXCL12 in the vicinity and lumen of these sinusoids is necessary to abolish any possible CXCL12-mediated retention of CXCR4+ leukocytes. Here we propose to uncover the contribution of ACKR3 in the trafficking of leukocytes through the sinusoids in the spleen. About half of MZBs express ACKR3 and possess a transcriptome that markedly differs from the one in found in cells that are devoid of ACKR3. Expression of the receptor correlates with the capability of adoptively transferred follicular B cells to upregulate ACKR3 and to survive and replenish the MZ of CD19 deficient recipients, which do not contain functional MZBs. We propose to unveil the role of ACKR3 expression on MZB for antigen deposition on FDCs and the efficiency of a humoral immune response. The expression and scavenging activity of ACKR3 on FDCs could contribute to the local confinement of the CXCL12 gradients in germinal centers (GCs). The two chemokines CXCL12 and CXCL13 via their cognate receptors CXC4 and CXCR5, respectively organize B cell trafficking between the light and dark zone. We speculate that knock down of ACKR3 in FDCs may unbalance B cell distribution and negatively influence an efficient humoral immune response. Altogether the proposed investigations shall provide new insights on the role of ACKR3 for immune responses.