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|Title:||CCX-CKR deficiency alters thymic stroma impairing thymocyte development and promoting autoimmunity|
|Citation:||Blood, 2013; 121(1):118-128|
|Publisher:||Amer Soc Hematology|
|Mark D. Bunting, Iain Comerford, Natalie Seach, Maree V. Hammett, Darren L. Asquith, Heinrich Körner, Richard L. Boyd, Robert J. B. Nibbs, and Shaun R. McColl|
|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.|
|Keywords:||Submandibular Gland; Liver; Kidney; Thymus Gland; Epithelial Cells; Stem Cells; Animals; Mice, Knockout; Mice; Sjogren's Syndrome; Disease Models, Animal; Receptors, Chemokine; Chemokines; Chemokines, CC; Immunophenotyping; Lymphopoiesis; Autoimmunity; Self Tolerance; Male; Receptors, CCR7; Adaptive Immunity; Thymocytes|
|Rights:||© 2013 by The American Society of Hematology|
|Appears in Collections:||IPAS publications|
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