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

Huihui Chen; Kin Sang Cho; T. H.Khanh Vu; Ching Hung Shen; Mandeep Kaur; Guochun Chen; Rose Mathew; M. Lisa McHam; Ahad Fazelat; Kameran Lashkari; Ngan Pan Bennett Au; Joyce Ka Yu Tse; Yingqian Li; Honghua Yu; Lanbo Yang; Joan Stein-Streilein; Chi Him Eddie Ma; Clifford J. Woolf; Mark T. Whary; Martine J. Jager; James G. Fox; Jianzhu Chen; Dong F. Chen

doi:10.1038/s41467-018-05681-9

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

Huihui Chen, Kin Sang Cho, T. H.Khanh Vu, Ching Hung Shen, Mandeep Kaur, Guochun Chen, Rose Mathew, M. Lisa McHam, Ahad Fazelat, Kameran Lashkari, Ngan Pan Bennett Au, Joyce Ka Yu Tse, Yingqian Li, Honghua Yu, Lanbo Yang, Joan Stein-Streilein, Chi Him Eddie Ma, Clifford J. Woolf, Mark T. Whary, Martine J. JagerJames G. Fox, Jianzhu Chen, Dong F. Chen^*

^*Corresponding author for this work

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Abstract

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-sensitized by exposure to commensal microflora.

Original language	English
Article number	3209
Number of pages	13
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05681-9
Publication status	Published - 10 Aug 2018

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Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucomaFinal published version, 1.55 MBLicence: CC BY

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Chen, 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., ... Chen, D. F. (2018). Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma. Nature Communications, 9(1), Article 3209. https://doi.org/10.1038/s41467-018-05681-9

@article{2576d8b70f4a4bf08161fd777c314104,

title = "Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma",

abstract = "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-sensitized by exposure to commensal microflora.",

author = "Huihui Chen and Cho, {Kin Sang} and Vu, {T. H.Khanh} and Shen, {Ching Hung} and Mandeep Kaur and Guochun Chen and Rose Mathew and McHam, {M. Lisa} and Ahad Fazelat and Kameran Lashkari and Au, {Ngan Pan Bennett} and Tse, {Joyce Ka Yu} and Yingqian Li and Honghua Yu and Lanbo Yang and Joan Stein-Streilein and Ma, {Chi Him Eddie} and Woolf, {Clifford J.} and Whary, {Mark T.} and Jager, {Martine J.} and Fox, {James G.} and Jianzhu Chen and Chen, {Dong F.}",

note = "Funding Information: We thank Randy Huang of the Schepens Eye Research Institute Flow Cytometry Core Facility for assistant in data analysis, Eric Zhao for schematic graphic design, and MIT technicians Carlos Umana, Oscar Acevedo, and Allan Discua for performing the embryo transfer and maintaining the GF and ASF mice. This work was supported by grants from the National Institutes of Health (EY025913, EY027067, and EY025259; NS038253; and AI69208), Lion{\textquoteright}s Foundation, Miriam and Sheldon Adelson Medical Research Foundation, the National Nature Science Foundation of China (81200683 and 20120162), the Ivan R. Cottrell Professorship and Research Fund, Oogfonds/StichtingGlaucoomfonds/ SNOO/LOOF/Nelly Reef Fund/Prins Bernhard Cultuur Fonds, the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute, and the NEI Core Grant for Vision Research (P30 EY03790). Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = aug,

day = "10",

doi = "10.1038/s41467-018-05681-9",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Chen, H, Cho, KS, Vu, THK, Shen, CH, Kaur, M, Chen, G, Mathew, R, McHam, ML, Fazelat, A, Lashkari, K, Au, NPB, Tse, JKY, Li, Y, Yu, H, Yang, L, Stein-Streilein, J, Ma, CHE, Woolf, CJ, Whary, MT, Jager, MJ, Fox, JG, Chen, J & Chen, DF 2018, 'Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma', Nature Communications, vol. 9, no. 1, 3209. https://doi.org/10.1038/s41467-018-05681-9

TY - JOUR

T1 - Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma

AU - Chen, Huihui

AU - Cho, Kin Sang

AU - Vu, T. H.Khanh

AU - Shen, Ching Hung

AU - Kaur, Mandeep

AU - Chen, Guochun

AU - Mathew, Rose

AU - McHam, M. Lisa

AU - Fazelat, Ahad

AU - Lashkari, Kameran

AU - Au, Ngan Pan Bennett

AU - Tse, Joyce Ka Yu

AU - Li, Yingqian

AU - Yu, Honghua

AU - Yang, Lanbo

AU - Stein-Streilein, Joan

AU - Ma, Chi Him Eddie

AU - Woolf, Clifford J.

AU - Whary, Mark T.

AU - Jager, Martine J.

AU - Fox, James G.

AU - Chen, Jianzhu

AU - Chen, Dong F.

N1 - Funding Information: We thank Randy Huang of the Schepens Eye Research Institute Flow Cytometry Core Facility for assistant in data analysis, Eric Zhao for schematic graphic design, and MIT technicians Carlos Umana, Oscar Acevedo, and Allan Discua for performing the embryo transfer and maintaining the GF and ASF mice. This work was supported by grants from the National Institutes of Health (EY025913, EY027067, and EY025259; NS038253; and AI69208), Lion’s Foundation, Miriam and Sheldon Adelson Medical Research Foundation, the National Nature Science Foundation of China (81200683 and 20120162), the Ivan R. Cottrell Professorship and Research Fund, Oogfonds/StichtingGlaucoomfonds/ SNOO/LOOF/Nelly Reef Fund/Prins Bernhard Cultuur Fonds, the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute, and the NEI Core Grant for Vision Research (P30 EY03790). Publisher Copyright: © 2018, The Author(s).

PY - 2018/8/10

Y1 - 2018/8/10

N2 - 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-sensitized by exposure to commensal microflora.

AB - 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-sensitized by exposure to commensal microflora.

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U2 - 10.1038/s41467-018-05681-9

DO - 10.1038/s41467-018-05681-9

M3 - Article

C2 - 30097565

AN - SCOPUS:85051431773

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3209

ER -

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

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