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https://hdl.handle.net/2440/77427
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Type: | Journal article |
Title: | CCX-CKR deficiency alters thymic stroma impairing thymocyte development and promoting autoimmunity |
Author: | Bunting, M. Comerford, I. Seach, N. Hammett, M. Asquith, D. Korner, H. Boyd, R. Nibbs, R. McColl, S. |
Citation: | Blood, 2013; 121(1):118-128 |
Publisher: | Amer Soc Hematology |
Issue Date: | 2013 |
ISSN: | 0006-4971 1528-0020 |
Statement of Responsibility: | 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 |
DOI: | 10.1182/blood-2012-06-434886 |
Grant ID: | NHMRC ARC NHMRC |
Published version: | http://dx.doi.org/10.1182/blood-2012-06-434886 |
Appears in Collections: | Aurora harvest 4 IPAS publications |
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