Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma

Chen, H.H.; Cho, K.S.; Vu, T.H.K.; Shen, C.H.; Kaur, M.; Chen, G.; Mathew, R.; Mcham, M.L.; Fazelat, A.; Lashkari, K.; Au, N.P.B.; Tse, J.K.Y.; Li, Y.; Yu, H.; Yang, L.; Stein-Streilein, J.; Ma, C.H.E.; Woolf, C.J.; Whary, M.T.; Jager, M.J.; Fox, J.G.; Chen, J.Z.; Chen, D.F.

doi:doi:10.1038/s41467-018-05681-9

Glaucoma is the most prevalent neurodegenerative disease and a leading cause of blindness worldwide. The mechanisms causing glaucomatous neurodegeneration are not fully understood. Here we show, using mice deficient in T and/or B cells and adoptive cell transfer, that transient elevation of intraocular pressure (IOP) is sufficient to induce T-cell infiltration into the retina. This T-cell infiltration leads to a prolonged phase of retinal ganglion cell degeneration that persists after IOP returns to a normal level. Heat shock proteins (HSP) are identified as target antigens of T-cell responses in glaucomatous mice and human glaucoma patients. Furthermore, retina-infiltrating T cells cross-react with human and bacterial HSPs; mice raised in the absence of commensal microflora do not develop glaucomatous T-cell responses or the associated neurodegeneration. These results provide compelling evidence that glaucomatous neurodegeneration is mediated in part by T cells that are pre...Show moreGlaucoma is the most prevalent neurodegenerative disease and a leading cause of blindness worldwide. The mechanisms causing glaucomatous neurodegeneration are not fully understood. Here we show, using mice deficient in T and/or B cells and adoptive cell transfer, that transient elevation of intraocular pressure (IOP) is sufficient to induce T-cell infiltration into the retina. This T-cell infiltration leads to a prolonged phase of retinal ganglion cell degeneration that persists after IOP returns to a normal level. Heat shock proteins (HSP) are identified as target antigens of T-cell responses in glaucomatous mice and human glaucoma patients. Furthermore, retina-infiltrating T cells cross-react with human and bacterial HSPs; mice raised in the absence of commensal microflora do not develop glaucomatous T-cell responses or the associated neurodegeneration. These results provide compelling evidence that glaucomatous neurodegeneration is mediated in part by T cells that are pre-sensitized by exposure to commensal microflora.
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Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma