title: CCX-CKR deficiency alters thymic stroma impairing thymocyte development and promoting autoimmunity.
abstract: The atypical chemokine receptor CCX-CKR regulates bioavailability of CCL19, CCL21, and CCL25, homeostatic chemokines that play crucial roles in thymic lymphopoiesis. Deletion of CCX-CKR results in accelerated experimental autoimmunity induced by immunization. Here we show that CCX-CKR deletion also increases incidence of a spontaneous Sjögren's syndrome-like pathology, characterized by lymphocytic infiltrates in salivary glands and liver of CCX-CKR(-/-) mice, suggestive of a defect in self-tolerance when CCX-CKR is deleted. This prompted detailed examination of the thymus in CCX-CKR(-/-) mice. Negatively selected mature SP cells were less abundant in CCX-CKR(-/-) thymi, yet expansion of both DP and immature SP cells was apparent. Deletion of CCX-CKR also profoundly reduced proportions of DN3 thymocyte precursors and caused DN2 cells to accumulate within the medulla. These effects are likely driven by alterations in thymic stroma as CCX-CKR(-/-) mice have fewer cTECs per thymocyte, and cTECs express the highest level of CCX-CKR in the thymus. A profound decrease in CCL25 within the thymic cortex was observed in CCX-CKR(-/-) thymi, likely accounting for their defects in thymocyte distribution and frequency. These findings identify a novel role for CCX-CKR in regulating cTEC biology, which promotes optimal thymocyte development and selection important for self-tolerant adaptive immunity.
authors.affiliation: Chemokine Biology Laboratory, School of Molecular and Biomedical Science, University of Adelaide and Centre for Molecular Pathology, Adelaide, South Australia, Australia.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Bunting
authors.forename: Iain
authors.initials: I
authors.lastname: Comerford
authors.forename: Natalie
authors.initials: N
authors.lastname: Seach
authors.forename: Maree V
authors.initials: MV
authors.lastname: Hammett
authors.forename: Darren L
authors.initials: DL
authors.lastname: Asquith
authors.forename: Heinrich
authors.initials: H
authors.lastname: Körner
authors.forename: Richard L
authors.initials: RL
authors.lastname: Boyd
authors.forename: Robert J B
authors.initials: RJ
authors.lastname: Nibbs
authors.forename: Shaun R
authors.initials: SR
authors.lastname: McColl
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics / Q000276:immunology; D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D019742:Chemokines, CC / Q000096:biosynthesis; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D016130:Immunophenotyping; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D038041:Lymphopoiesis / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D054400:Receptors, CCR7 / Q000172:deficiency / Q000235:genetics; D019707:Receptors, Chemokine / Q000172:deficiency* / Q000235:genetics / Q000276:immunology / Q000502:physiology; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology; D012859:Sjogren's Syndrome / Q000235:genetics / Q000473:pathology; D013234:Stem Cells / Q000145:classification / Q000378:metabolism / Q000473:pathology; D013363:Submandibular Gland / Q000473:pathology; D060168:Thymocytes / Q000473:pathology*; D013950:Thymus Gland / Q000473:pathology*; D000097628:Chemokine Receptor D6
chemical_list: D018925:Chemokines; D019742:Chemokines, CC; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; C515709:Ackr2 protein, mouse; D000097628:Chemokine Receptor D6; C491541:Ccl25 protein, mouse; C515371:Ccr7 protein, mouse