Desiccating stress-induced chemokine expression in the epithelium is dependent on upregulation of NKG2D/RAE-1 and release of IFN-γ in experimental dry eye

J Immunol. 2014 Nov 15;193(10):5264-72. doi: 10.4049/jimmunol.1400016. Epub 2014 Oct 6.


The Th1-associated chemokines CXCL9, CXCL10, and CXCL11 coordinate migration of CXCR3(+) Th1 cells. The objective of this study was to evaluate the role of the innate immune system in stimulating chemokine expression in an experimental model of dry eye and bridge the gap between innate and adaptive immunity. Desiccating stress (DS) induced very early (6 h) expression and production of Th1-associated chemokines in cornea and conjunctiva of C57BL/6 and RAG1 knockout (KO) mice, demonstrating that chemokine expression does not require innate T cells. We then demonstrated that activating the innate immune system prior to adoptive transfer of T cells to RAG1KO mice increased disease severity. Interestingly, lack of induction of chemokines CXCL9, CXCL10, and CXCL11 in IFN-γKO mice provided evidence that their expression requires IFN-γ for induction. Treatment of RAG1KO mice with anti-NK1.1 prevented the increase of CXCL9, CXCL10, and CXCL11 in response to DS, compared with isotype controls. Additionally, DS increased the expression of NKG2D in the conjunctiva. The expression of the NKG2D ligand, retinoic acid early inducible gene 1, also increased at the ocular surface at both the protein and gene levels. Neutralization of NKG2D at the ocular surface decreased the expression of CXCL9, CXCL10, CXCL11, and IFN-γ. In summary, upregulation of CXCL9, CXCL10, and CXCL11 expression in experimental dry eye is T cell-independent, requiring IFN-γ-producing NKG2D(+) NK cells that are activated in response to DS-induced stress signals. This study provides insight into the events that trigger the initial immune response in dry eye pathology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antibodies / pharmacology
  • Antigens, Ly / genetics
  • Antigens, Ly / immunology
  • Chemokine CXCL10 / genetics
  • Chemokine CXCL10 / immunology
  • Chemokine CXCL11 / genetics
  • Chemokine CXCL11 / immunology
  • Chemokine CXCL9 / genetics
  • Chemokine CXCL9 / immunology
  • Conjunctiva / immunology
  • Conjunctiva / pathology
  • Desiccation
  • Disease Models, Animal
  • Epithelium, Corneal / immunology*
  • Epithelium, Corneal / pathology
  • Female
  • Gene Deletion
  • Gene Expression Regulation
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / immunology
  • Immunity, Innate*
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology*
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NK Cell Lectin-Like Receptor Subfamily B / antagonists & inhibitors
  • NK Cell Lectin-Like Receptor Subfamily B / genetics
  • NK Cell Lectin-Like Receptor Subfamily B / immunology
  • NK Cell Lectin-Like Receptor Subfamily K / genetics
  • NK Cell Lectin-Like Receptor Subfamily K / immunology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology
  • T-Lymphocytes / transplantation
  • Xerophthalmia / genetics
  • Xerophthalmia / immunology*
  • Xerophthalmia / pathology


  • Antibodies
  • Antigens, Ly
  • Chemokine CXCL10
  • Chemokine CXCL11
  • Chemokine CXCL9
  • Cxcl10 protein, mouse
  • Cxcl11 protein, mouse
  • Cxcl9 protein, mouse
  • Homeodomain Proteins
  • Klrb1c protein, mouse
  • Klrk1 protein, mouse
  • Membrane Proteins
  • NK Cell Lectin-Like Receptor Subfamily B
  • NK Cell Lectin-Like Receptor Subfamily K
  • Raet1a protein, mouse
  • RAG-1 protein
  • Interferon-gamma