The role of ACKR3 in Cell Physiology and Pathology

Chemokine receptors have a central role in orchestrating cell and cell-niche interaction. This interaction is crucial in maintaining immune homeostasis and organogenesis. The expression level of the chemokine receptors and the concentration of cognate ligands in the milieu determines the biological output of the cells such as migration, proliferation, and differentiation. Any alteration in the intensity of signals transduced by binding of the chemokine receptors to the cognate ligand or as the result of co-opting the signal from other surface receptors affects the fate decision by cells. ACKR3 is an atypical chemokine receptor that was initially regarded as a scavenger for the chemokine CXCL12. Later, its function was extended beyond chemoattraction by studies indicating the upregulation of ACKR3 in multiple cancers. In the context of cancer, the overexpression of ACKR3 promotes angiogenesis and malignant transformation of cells. Despite extensive research that has been conducted to delineate the functionality of ACKR3 in various types of cancers, the exact role of this receptor in immune cells and its potential impact on immune responses remained to be addressed. The lack of knowledge was correlated to the debate on the expression pattern and actual function of ACKR3 in immune cells. The conflicting results were basically due to the inconsistency between the mRNA and protein data, the nonspecific commercial monoclonal antibodies (mAb) available in the market, and the physiological distinctions among different subsets of immune cells, which are largely defined by the developmental stages of the cells and their location. The intrinsic physiological differences in coordination with the cues provided by local microenvironment affect the dynamics of chemokine receptor expression, and this per se creates further ambiguity about the expression pattern of ACKR3 by immune cells. In this thesis this debate, using different transgenic mouse models, was addressed. My work show