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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
Statement of
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
Thymus Gland
Epithelial Cells
Stem Cells
Mice, Knockout
Sjogren's Syndrome
Disease Models, Animal
Receptors, Chemokine
Chemokines, CC
Self Tolerance
Receptors, CCR7
Adaptive Immunity
Rights: © 2013 by The American Society of Hematology
DOI: 10.1182/blood-2012-06-434886
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