CCX-CKR deficiency alters thymic stroma impairing thymocyte development and promoting autoimmunity

Bunting, M.D., Comerford, I., Seach, N., Hammett, M. V., Asquith, D.L., Korner, H., Boyd, R. L., Nibbs, R.J.B. and McColl, S. R. (2013) CCX-CKR deficiency alters thymic stroma impairing thymocyte development and promoting autoimmunity. Blood, 121(1), pp. 118-128. (doi: 10.1182/blood-2012-06-434886)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Asquith, Dr Darren and Nibbs, Professor Rob
Authors: Bunting, M.D., Comerford, I., Seach, N., Hammett, M. V., Asquith, D.L., Korner, H., Boyd, R. L., Nibbs, R.J.B., and McColl, S. R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Blood
ISSN:0006-4971
ISSN (Online):1528-0020
Published Online:14 November 2012

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