OpenLB
Open Library of Bioscience
Advanced Search
Proceedings of the National Academy of Sciences of the United States of America
Nov 26, 2024;121 (48): e2407648121.

CD4 T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model.

Alexia Vereertbrugghen, Manuela Pizzano, Agostina Cernutto, Florencia Sabbione, Irene A Keitelman, Douglas Vera Aguilar, Ariel Podhorzer, Federico Fuentes, Celia Corral-V��zquez, Mauricio Guzm��n, Mirta N Giordano, Anal��a Trevani, Cintia S de Paiva, Jerem��as G Galletti
Author Information
  1. Alexia Vereertbrugghen: Innate Immunity Laboratory, Institute of Experimental Medicine (National Scientific and Technical Research Council/National Academy of Medicine of Buenos Aires), Buenos Aires 1425, Argentina. ORCID
  2. Manuela Pizzano: Innate Immunity Laboratory, Institute of Experimental Medicine (National Scientific and Technical Research Council/National Academy of Medicine of Buenos Aires), Buenos Aires 1425, Argentina.
  3. Agostina Cernutto: Innate Immunity Laboratory, Institute of Experimental Medicine (National Scientific and Technical Research Council/National Academy of Medicine of Buenos Aires), Buenos Aires 1425, Argentina.
  4. Florencia Sabbione: Innate Immunity Laboratory, Institute of Experimental Medicine (National Scientific and Technical Research Council/National Academy of Medicine of Buenos Aires), Buenos Aires 1425, Argentina.
  5. Irene A Keitelman: Innate Immunity Laboratory, Institute of Experimental Medicine (National Scientific and Technical Research Council/National Academy of Medicine of Buenos Aires), Buenos Aires 1425, Argentina.
  6. Douglas Vera Aguilar: Innate Immunity Laboratory, Institute of Experimental Medicine (National Scientific and Technical Research Council/National Academy of Medicine of Buenos Aires), Buenos Aires 1425, Argentina.
  7. Ariel Podhorzer: Flow Cytometry Unit, Institute of Experimental Medicine (National Scientific and Technical Research Council/National Academy of Medicine of Buenos Aires), Buenos Aires 1425, Argentina. ORCID
  8. Federico Fuentes: Confocal Microscopy Unit, Institute of Experimental Medicine (National Scientific and Technical Research Council/National Academy of Medicine of Buenos Aires), Buenos Aires 1425, Argentina.
  9. Celia Corral-V��zquez: Translational Clinical Research Program, Hospital del Mar Research Institute, Barcelona 08003, Spain.
  10. Mauricio Guzm��n: Translational Clinical Research Program, Hospital del Mar Research Institute, Barcelona 08003, Spain. ORCID
  11. Mirta N Giordano: Innate Immunity Laboratory, Institute of Experimental Medicine (National Scientific and Technical Research Council/National Academy of Medicine of Buenos Aires), Buenos Aires 1425, Argentina.
  12. Anal��a Trevani: Innate Immunity Laboratory, Institute of Experimental Medicine (National Scientific and Technical Research Council/National Academy of Medicine of Buenos Aires), Buenos Aires 1425, Argentina.
  13. Cintia S de Paiva: Ocular Surface Center, Baylor College of Medicine, Houston, TX 77030. ORCID
  14. Jerem��as G Galletti: Innate Immunity Laboratory, Institute of Experimental Medicine (National Scientific and Technical Research Council/National Academy of Medicine of Buenos Aires), Buenos Aires 1425, Argentina. ORCID
PMID: 39560641 DOI: 10.1073/pnas.2407648121

Abstract

Dry eye disease (DED) is characterized by a dysfunctional tear film in which the corneal epithelium and its abundant nerves are affected by ocular desiccation and inflammation. Although adaptive immunity and specifically CD4 T cells play a role in DED pathogenesis, the exact contribution of these cells to corneal epithelial and neural damage remains undetermined. To address this, we explored the progression of a surgical DED model in wild-type (WT) and T cell-deficient mice. We observed that adaptive immune-deficient mice developed all aspects of DED comparably to WT mice except for the absence of functional and morphological corneal nerve changes, nerve damage-associated transcriptomic signature in the trigeminal ganglia, and sustained tear cytokine levels. Adoptive transfer of CD4 T cells from WT DED mice to T cell-deficient mice reproduced corneal nerve damage but not epitheliopathy. Conversely, T cell-deficient mice reconstituted solely with na��ve CD4 T cells developed corneal nerve impairment and epitheliopathy upon DED induction, thus replicating the WT DED phenotype. Collectively, our data show that while corneal neuropathy is driven by CD4 T cells in DED, corneal epithelial damage develops independently of the adaptive immune response. These findings have implications for T cell-targeting therapies currently in use for DED.

Keywords

CD4 T cells autoimmunity cornea neuropathy ocular surface

References

  1. J Immunol. 2014 Nov 15;193(10):5264-72 [PMID: 25288568]
  2. Front Med (Lausanne). 2022 Mar 23;9:849990 [PMID: 35402439]
  3. Am J Pathol. 2011 Oct;179(4):1807-14 [PMID: 21843497]
  4. Front Cell Neurosci. 2022 Jun 02;16:885569 [PMID: 35722619]
  5. J Ocul Pharmacol Ther. 2020 Apr;36(3):137-146 [PMID: 32175799]
  6. Am J Pathol. 2014 Jun;184(6):1652-9 [PMID: 24828391]
  7. Ocul Surf. 2017 Jul;15(3):575-628 [PMID: 28736343]
  8. Ocul Surf. 2017 Jul;15(3):276-283 [PMID: 28736335]
  9. Indian J Ophthalmol. 2023 Apr;71(4):1190-1202 [PMID: 37026250]
  10. Elife. 2019 Aug 15;8: [PMID: 31414985]
  11. Cell Rep. 2022 May 24;39(8):110852 [PMID: 35613584]
  12. Invest Ophthalmol Vis Sci. 2011 Aug 09;52(9):6279-85 [PMID: 21474767]
  13. BMC Ophthalmol. 2021 May 12;21(1):211 [PMID: 33980205]
  14. Brain Res Bull. 2022 Sep;187:122-137 [PMID: 35781031]
  15. Front Mol Neurosci. 2022 Aug 31;15:990260 [PMID: 36117915]
  16. Exp Eye Res. 2018 Apr;169:91-98 [PMID: 29407221]
  17. Exp Eye Res. 2016 Oct;151:19-22 [PMID: 27443502]
  18. Immunology. 2017 Apr;150(4):397-407 [PMID: 28108991]
  19. J Immunol. 2006 Apr 1;176(7):3950-7 [PMID: 16547229]
  20. Ocul Surf. 2018 Jan;16(1):31-44 [PMID: 29031645]
  21. Invest Ophthalmol Vis Sci. 2014 Aug 19;55(9):5871-7 [PMID: 25139737]
  22. Int Immunol. 2016 Apr;28(4):163-71 [PMID: 26874355]
  23. J Allergy Clin Immunol. 2015 Mar;135(3):626-35 [PMID: 25528359]
  24. J Immunol. 2016 Nov 1;197(9):3464-3470 [PMID: 27655846]
  25. Front Cell Dev Biol. 2022 Mar 08;10:824036 [PMID: 35350379]
  26. Mucosal Immunol. 2024 Jun;17(3):491-507 [PMID: 38007004]
  27. Cont Lens Anterior Eye. 2021 Apr;44(2):132-156 [PMID: 33775375]
  28. Invest Ophthalmol Vis Sci. 2023 Mar 1;64(3):34 [PMID: 36988949]
  29. Indian J Ophthalmol. 2023 Apr;71(4):1276-1284 [PMID: 37026259]
  30. eNeuro. 2019 Apr 1;6(2): [PMID: 30957012]
  31. Invest Ophthalmol Vis Sci. 2007 Jun;48(6):2553-60 [PMID: 17525184]
  32. JAMA Ophthalmol. 2017 Jul 1;135(7):795-800 [PMID: 28594979]
  33. Proc Natl Acad Sci U S A. 2023 Aug;120(31):e2217795120 [PMID: 37487076]
  34. Ophthalmology. 1997 Feb;104(2):223-35 [PMID: 9052626]
  35. Cell Death Discov. 2023 Jun 30;9(1):209 [PMID: 37391421]
  36. Eye (Lond). 2023 Oct;37(14):2950-2955 [PMID: 36808180]
  37. Elife. 2023 May 31;12: [PMID: 37254842]
  38. Invest Ophthalmol Vis Sci. 2016 Sep 1;57(11):4824-4830 [PMID: 27654409]
  39. Front Pain Res (Lausanne). 2023 Oct 31;4:1274811 [PMID: 38028432]
  40. Pain. 2020 Jul;161(7):1542-1554 [PMID: 32107361]
  41. Ocul Surf. 2018 Jul;16(3):368-376 [PMID: 29772277]
  42. Neuroscience. 2020 Aug 21;442:274-285 [PMID: 32592826]
  43. Glia. 2017 Jun;65(6):851-863 [PMID: 27878997]
  44. J Immunol. 2011 Oct 1;187(7):3653-62 [PMID: 21880984]
  45. Int J Mol Sci. 2020 Dec 04;21(23): [PMID: 33291796]
  46. Front Mol Neurosci. 2018 Jun 26;11:219 [PMID: 29997476]
  47. J Immunol. 2015 Oct 1;195(7):3086-99 [PMID: 26324767]
  48. BMC Ophthalmol. 2018 Dec 4;18(1):309 [PMID: 30514255]
  49. Blood. 2011 Oct 27;118(17):4630-4 [PMID: 21908425]
  50. Mucosal Immunol. 2014 Mar;7(2):417-27 [PMID: 24022789]
  51. Prog Retin Eye Res. 2015 Jan;44:36-61 [PMID: 25461622]
  52. Mucosal Immunol. 2017 Sep;10(5):1202-1210 [PMID: 28051088]
  53. Arch Ophthalmol. 2012 Jan;130(1):90-100 [PMID: 22232476]
  54. J Leukoc Biol. 2011 Jun;89(6):965-72 [PMID: 21402771]
  55. J Neuroinflammation. 2023 May 22;20(1):120 [PMID: 37217914]
  56. Invest Ophthalmol Vis Sci. 2013 Jun 12;54(6):4081-91 [PMID: 23702781]
  57. Invest Ophthalmol Vis Sci. 2012 Apr 24;53(4):2062-75 [PMID: 22395876]
  58. Exp Eye Res. 2022 Sep;222:109191 [PMID: 35850173]
  59. Exp Eye Res. 2009 Aug;89(2):166-71 [PMID: 19298814]
  60. Transl Psychiatry. 2013 Jul 09;3:e280 [PMID: 23838891]
  61. Front Cell Neurosci. 2020 Dec 10;14:610342 [PMID: 33362474]
  62. Invest Ophthalmol Vis Sci. 2009 Aug;50(8):3802-7 [PMID: 19339740]
  63. Am J Pathol. 2024 May;194(5):810-827 [PMID: 38325553]
  64. Am J Pathol. 2020 Jul;190(7):1474-1482 [PMID: 32289288]
  65. Saudi J Ophthalmol. 2022 Feb 18;35(2):131-139 [PMID: 35391807]
  66. FASEB J. 2019 Mar;33(3):4598-4609 [PMID: 30561223]
  67. Alzheimers Dement (N Y). 2019 Jun 04;5:175-183 [PMID: 31194017]
  68. Mucosal Immunol. 2009 May;2(3):243-53 [PMID: 19242409]
  69. Exp Eye Res. 2013 Dec;117:118-25 [PMID: 24012834]
  70. Ocul Surf. 2022 Jan;23:40-48 [PMID: 34781021]
  71. Mucosal Immunol. 2022 Apr;15(4):620-628 [PMID: 35361907]
  72. Invest Ophthalmol Vis Sci. 2002 Aug;43(8):2609-14 [PMID: 12147592]
  73. Eur J Ophthalmol. 2003 Mar;13(2):115-27 [PMID: 12696629]
  74. Mucosal Immunol. 2014 Jan;7(1):38-45 [PMID: 23571503]
  75. Nat Rev Immunol. 2018 Sep;18(9):545-558 [PMID: 29921905]
  76. Exp Eye Res. 2014 Jan;118:117-24 [PMID: 24315969]
  77. Proc Natl Acad Sci U S A. 2022 Jan 25;119(4): [PMID: 35058362]
  78. Nat Rev Immunol. 2023 Jan;23(1):38-54 [PMID: 35790881]
  79. PLoS One. 2012;7(5):e36822 [PMID: 22590618]
  80. Immunology. 2020 Oct;161(2):148-161 [PMID: 32702135]
  81. Cornea. 2014 Dec;33(12):1336-41 [PMID: 25255136]
  82. Mol Pain. 2016 Oct 4;12: [PMID: 27702909]
  83. Front Neurosci. 2015 Sep 09;9:318 [PMID: 26441494]
  84. Ocul Surf. 2017 Jul;15(3):438-510 [PMID: 28736340]
  85. Exp Eye Res. 2020 Dec;201:108294 [PMID: 33039458]

Grants

  1. R01 EY035333/NEI NIH HHS
  2. U01 EY034692/NEI NIH HHS
  3. PICT 2018-02911 PICT 2020-00138 PICT 2021-00109/Agencia Nacional de Promoci��n de la Investigaci��n, el Desarrollo Tecnol��gico y la Innovaci��n (Agencia I + D + i)
  4. 221859/Z/20/Z/Wellcome Trust (WT)
  5. /Wellcome Trust

MeSH Term

Animals
Dry Eye Syndromes
CD4-Positive T-Lymphocytes
Mice
Disease Models, Animal
Epithelium, Corneal
Cornea
Tears
Mice, Inbred C57BL
Adoptive Transfer
Cytokines
Female

Chemicals

Cytokines
Journal Article
Article has an altmetric score of 6

Word Cloud

Created with Highcharts 10.0.0TDEDcornealcellsCD4micenervedamageWTadaptivecell-deficientepitheliopathyeyetearocularepithelialmodeldevelopedneuropathyDrydiseasecharacterizeddysfunctionalfilmepitheliumabundantnervesaffecteddesiccationinflammationAlthoughimmunityspecificallyplayrolepathogenesisexactcontributionneuralremainsundeterminedaddressexploredprogressionsurgicalwild-typeobservedimmune-deficientaspectscomparablyexceptabsencefunctionalmorphologicalchangesdamage-associatedtranscriptomicsignaturetrigeminalgangliasustainedcytokinelevelsAdoptivetransferreproducedConverselyreconstitutedsolelyna��veimpairmentuponinductionthusreplicatingphenotypeCollectivelydatashowdrivendevelopsindependentlyimmuneresponsefindingsimplicationscell-targetingtherapiescurrentlyusedriveacuteaqueous-deficientdryautoimmunitycorneasurface

Similar Articles

Cited By

No available data.