June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
MHC class II positive retinal microglia exacerbate uveitis by activating infiltrating T cells
Author Affiliations & Notes
  • Shintaro Shirahama
    Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • May Yue Lee
    Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Yoko Okunuki
    Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Kip M Connor
    Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Meredith S Gregory-Ksander
    Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Bruce Ksander
    Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Shintaro Shirahama None; May Lee None; Yoko Okunuki None; Kip Connor None; Meredith Gregory-Ksander None; Bruce Ksander None
  • Footnotes
    Support  R01EY031291
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 2684. doi:
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    • Get Citation

      Shintaro Shirahama, May Yue Lee, Yoko Okunuki, Kip M Connor, Meredith S Gregory-Ksander, Bruce Ksander; MHC class II positive retinal microglia exacerbate uveitis by activating infiltrating T cells. Invest. Ophthalmol. Vis. Sci. 2022;63(7):2684.

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

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Abstract

Purpose : Understanding the function of MHC class II positive (MHC-II+) antigen-presenting cells (APCs) is critical in understanding the pathogenesis of uveitis, which has two potential sources of APCs, retinal microglia and systemic macrophages. We previously published evidence that MHC-II+ microglia are not required for the induction of uveitic specific T cells. In the current study, we determine whether MHC-II+ microglia exacerbate uveitis by activating retina-infiltrating T cells.

Methods : EAU was induced by IRBP immunization of C57BL/6 mice, and the clinical score was determined by the standard method. FACS analysis was used to determine MHC-II expression on microglia (TMEM119 and P2RY12 antibodies). Knock-down of MHC-II specifically on microglia and not on systemic macrophages was achieved using an inducible knockout mouse (Tmem119-CreERT2 x MHC-IIflox/flox B6 mice; Tmem119-Cre KO mice) in which deletion of MHC-II was induced by tamoxifen and confirmed by FACS analysis. Adoptive transfer EAU was induced by harvesting T cells from the spleen and lymph nodes of donor mice at 14 days post-IRBP immunization and injecting i.p. (5 x 107 cells/mouse) into naïve recipients.

Results : During the first 10 days after induction of EAU, there was no increase in MHC-II+ retinal microglia (1.1 +/- 0.3%) as compared with retinas of naïve mice (0.7 +/- 0.3%). By contrast, in the later stage of EAU (day 20), there was a significant increase in the number of MHC-II+ Tmem119+ microglia (56.8 +/- 1.0%) within the retina. Similar results were obtained using P2RY12, another microglia specific antibody. Removal of MHC-II specifically from these retinal microglia and not from macrophages using inducible Tmem119-Cre KO mice significantly reduced the severity of the disease when the clinical score was compared with the frequency of MHC-II+ microglia (r=0.78, p=0.0036). To further confirm this, uveitic T cells from IRBP immunized WT mice were adoptively transferred into either MHC-IIflox/flox or Tmem119-Cre KO mice, resulting in a significant delay in the development of uveitis (p=0.03).

Conclusions : Our data indicate that MHC-II+ retinal microglia do not participate in the induction of uveitis but are important in the later stages where they exacerbate disease by activating retina-infiltrating T cells.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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