June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Corneal nerve damage in ocular graft-versus-host disease involves CXCR3+ exTh17 cells
Author Affiliations & Notes
  • Derek J Royer
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Hazem M Mousa
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Jose Echegaray
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Liwen Lin
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Victor L Perez
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Footnotes
    Commercial Relationships   Derek Royer, None; Hazem Mousa, None; Jose Echegaray, None; Liwen Lin, None; Victor Perez, None
  • Footnotes
    Support  R01EY024484, P30EY005722
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 2323. doi:
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    • Get Citation

      Derek J Royer, Hazem M Mousa, Jose Echegaray, Liwen Lin, Victor L Perez; Corneal nerve damage in ocular graft-versus-host disease involves CXCR3+ exTh17 cells. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2323.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Pathologic corneal nerve alterations can occur in patients with ocular graft-versus-host disease (oGVHD). Our group reported sensory nerve pathology is mediated by CXCR3+ donor CD4 T cells in a preclinical animal model of oGVHD. However, the mechanism remains unclear. Here, we tested the hypothesis that locally-expressed factors influence donor CD4 T cell function in oGVHD to promote corneal nerve damage.

Methods : Lethally irradiated C3-SW.H2b mice received bone marrow (BM) and T cells from allogeneic H2b-matched wild-type (WT) C57BL/6J mice to initiate GVHD. Control groups received BM only. Inflammatory gene signatures in the cornea were profiled by Nanostring prior to disease onset. Corneal nerve mechanosensation and pathology were assessed by Cochet-Bonnet esthesiometry and confocal microscopy with morphometric analysis. T cell phenotype/function was analyzed by flow cytometry. Pathomechanisms were explored by initiating oGVHD with T cells from CXCR3-/-, TNF-/-, and IL-17a-/- mice.

Results : Nanostring profiling revealed CXCR3 ligands among the most differentially expressed genes prior to oGVHD onset (p<0.01). Consistent with corneal sensation loss, intraepithelial nerve terminal loss was selectively observed in oGVHD if initiated with WT T cells. This pathology was attenuated upon induction with CXCR3-/- T cells (p<0.001). Accumulation of CXCR3+ CD4 T cells and Tbet+ RorγT+ exTh17 cells were observed in oGVHD target tissue when disease was initiated with WT but not CXCR3-/- T cells (p<0.01). Recruitment of Tbet+ Th1 and RorγT+ Th17 cells did not differ. Functional analysis revealed that CXCR3-/- CD4 T cells display altered cytokine expression compared to WT in oGVHD. Specifically, WT CD4 T cells exhibited greater cytokine polyfunctionality and TNF production than CXCR3-/- CD4 T cells (p<0.001). Finally, oGVHD was initiated with TNF-/- and IL-17a-/- T cells. T cell-derived TNF but not IL-17a was necessary to facilitate corneal sensation loss in oGVHD (p<0.001).

Conclusions : Corneal nerve damage in oGVHD correlated with CXCR3-dependent exTh17 cell infiltration. ExTh17 cells are characterized by broad cytokine expression and pathogenicity in many diseases. CXCR3 ligands expressed in the ocular surface microenvornment may influence exTh17 polarization and enhance TNF production. Taken together, these data implicate CXCR3 and TNF as potential targets to ameliorate corneal nerve pathology in oGVHD.

This is a 2020 ARVO Annual Meeting abstract.

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