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

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

Research output: Contribution to journalArticlepeer-review

32 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 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.

Original languageEnglish
Pages (from-to)118-28
Number of pages11
JournalBlood
Volume121
Issue number1
DOIs
Publication statusPublished or Issued - 3 Jan 2013
Externally publishedYes

Keywords

  • Adaptive Immunity/genetics
  • Animals
  • Autoimmunity/genetics
  • Chemokines/metabolism
  • Chemokines, CC/biosynthesis
  • Disease Models, Animal
  • Epithelial Cells/metabolism
  • Immunophenotyping
  • Kidney/pathology
  • Liver/pathology
  • Lymphopoiesis/genetics
  • Male
  • Mice
  • Mice, Knockout
  • Receptors, CCR7/deficiency
  • Receptors, Chemokine/deficiency
  • Self Tolerance/genetics
  • Sjogren's Syndrome/genetics
  • Stem Cells/classification
  • Submandibular Gland/pathology
  • Thymocytes/pathology
  • Thymus Gland/pathology

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