CCX-CKR deficiency alters thymic stroma impairing thymocyte development and promoting autoimmunity
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Bunting, MD and Comerford, I and Seach, N and Hammett, MV and Asquith, DL and Korner, H and Boyd, RL and Nibbs, RJB and McColl, SR, CCX-CKR deficiency alters thymic stroma impairing thymocyte development and promoting autoimmunity, Blood, 121, (1) pp. 118-128. ISSN 0006-4971 (2013) [Refereed Article]
Copyright 2013 American Society of Hematology
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. © 2013 by The American Society of Hematology.
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