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

Mark D Bunting, Iain Comerford, Natalie L Seach, Maree V Hammett, Darren L Asquith, Heinrich Korner, Richard L Boyd, Robert JB Nibbs, Shaun R McColl

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31 Citations (Scopus)

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 Sjogren s syndrome-like pathology, characterised 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.
Original languageEnglish
Pages (from-to)118 - 128
Number of pages11
JournalBlood
Volume121
Issue number1
DOIs
Publication statusPublished - 2013

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