T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis

Ruth J. Napier; Ellen J. Lee; Michael P. Davey; Emily E. Vance; João M. Furtado; Paige E. Snow; Kimberly A. Samson; Sydney J. Lashley; Brieanna R. Brown; Reiko Horai; Mary J. Mattapallil; Biying Xu; Michelle C. Callegan; Luke S. Uebelhoer; Christina L. Lancioni; Richard K. Vehe; Bryce A. Binstadt; Justine R. Smith; Rachel R. Caspi; Holly L. Rosenzweig

doi:10.1038/s41467-020-18961-0

T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis

Ruth J. Napier, Ellen J. Lee, Michael P. Davey, Emily E. Vance, João M. Furtado, Paige E. Snow, Kimberly A. Samson, Sydney J. Lashley, Brieanna R. Brown, Reiko Horai, Mary J. Mattapallil, Biying Xu, Michelle C. Callegan, Luke S. Uebelhoer, Christina L. Lancioni, Richard K. Vehe, Bryce A. Binstadt, Justine R. Smith, Rachel R. Caspi, Holly L. Rosenzweig

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) cause Blau syndrome, an inflammatory disorder characterized by uveitis. The antimicrobial functions of Nod2 are well-established, yet the cellular mechanisms by which dysregulated Nod2 causes uveitis remain unknown. Here, we report a non-conventional, T cell-intrinsic function for Nod2 in suppression of Th17 immunity and experimental uveitis. Reconstitution of lymphopenic hosts with Nod2^−/− CD4⁺ T cells or retina-specific autoreactive CD4⁺ T cells lacking Nod2 reveals a T cell-autonomous, Rip2-independent mechanism for Nod2 in uveitis. In naive animals, Nod2 operates downstream of TCR ligation to suppress activation of memory CD4⁺ T cells that associate with an autoreactive-like profile involving IL-17 and Ccr7. Interestingly, CD4⁺ T cells from two Blau syndrome patients show elevated IL-17 and increased CCR7. Our data define Nod2 as a T cell-intrinsic rheostat of Th17 immunity, and open new avenues for T cell-based therapies for Nod2-associated disorders such as Blau syndrome.

Original language	English (US)
Article number	5406
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-18961-0
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Napier, R. J., Lee, E. J., Davey, M. P., Vance, E. E., Furtado, J. M., Snow, P. E., Samson, K. A., Lashley, S. J., Brown, B. R., Horai, R., Mattapallil, M. J., Xu, B., Callegan, M. C., Uebelhoer, L. S., Lancioni, C. L., Vehe, R. K., Binstadt, B. A., Smith, J. R., Caspi, R. R., & Rosenzweig, H. L. (2020). T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis. Nature communications, 11(1), Article 5406. https://doi.org/10.1038/s41467-020-18961-0

Napier, RJ, Lee, EJ, Davey, MP, Vance, EE, Furtado, JM, Snow, PE, Samson, KA, Lashley, SJ, Brown, BR, Horai, R, Mattapallil, MJ, Xu, B, Callegan, MC, Uebelhoer, LS, Lancioni, CL, Vehe, RK, Binstadt, BA, Smith, JR, Caspi, RR & Rosenzweig, HL 2020, 'T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis', Nature communications, vol. 11, no. 1, 5406. https://doi.org/10.1038/s41467-020-18961-0

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title = "T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis",

abstract = "Mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) cause Blau syndrome, an inflammatory disorder characterized by uveitis. The antimicrobial functions of Nod2 are well-established, yet the cellular mechanisms by which dysregulated Nod2 causes uveitis remain unknown. Here, we report a non-conventional, T cell-intrinsic function for Nod2 in suppression of Th17 immunity and experimental uveitis. Reconstitution of lymphopenic hosts with Nod2−/− CD4+ T cells or retina-specific autoreactive CD4+ T cells lacking Nod2 reveals a T cell-autonomous, Rip2-independent mechanism for Nod2 in uveitis. In naive animals, Nod2 operates downstream of TCR ligation to suppress activation of memory CD4+ T cells that associate with an autoreactive-like profile involving IL-17 and Ccr7. Interestingly, CD4+ T cells from two Blau syndrome patients show elevated IL-17 and increased CCR7. Our data define Nod2 as a T cell-intrinsic rheostat of Th17 immunity, and open new avenues for T cell-based therapies for Nod2-associated disorders such as Blau syndrome.",

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AU - Furtado, João M.

AU - Snow, Paige E.

AU - Samson, Kimberly A.

AU - Lashley, Sydney J.

AU - Brown, Brieanna R.

AU - Horai, Reiko

AU - Mattapallil, Mary J.

AU - Xu, Biying

AU - Callegan, Michelle C.

AU - Uebelhoer, Luke S.

AU - Lancioni, Christina L.

AU - Vehe, Richard K.

AU - Binstadt, Bryce A.

AU - Smith, Justine R.

AU - Caspi, Rachel R.

AU - Rosenzweig, Holly L.

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N2 - Mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) cause Blau syndrome, an inflammatory disorder characterized by uveitis. The antimicrobial functions of Nod2 are well-established, yet the cellular mechanisms by which dysregulated Nod2 causes uveitis remain unknown. Here, we report a non-conventional, T cell-intrinsic function for Nod2 in suppression of Th17 immunity and experimental uveitis. Reconstitution of lymphopenic hosts with Nod2−/− CD4+ T cells or retina-specific autoreactive CD4+ T cells lacking Nod2 reveals a T cell-autonomous, Rip2-independent mechanism for Nod2 in uveitis. In naive animals, Nod2 operates downstream of TCR ligation to suppress activation of memory CD4+ T cells that associate with an autoreactive-like profile involving IL-17 and Ccr7. Interestingly, CD4+ T cells from two Blau syndrome patients show elevated IL-17 and increased CCR7. Our data define Nod2 as a T cell-intrinsic rheostat of Th17 immunity, and open new avenues for T cell-based therapies for Nod2-associated disorders such as Blau syndrome.

AB - Mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) cause Blau syndrome, an inflammatory disorder characterized by uveitis. The antimicrobial functions of Nod2 are well-established, yet the cellular mechanisms by which dysregulated Nod2 causes uveitis remain unknown. Here, we report a non-conventional, T cell-intrinsic function for Nod2 in suppression of Th17 immunity and experimental uveitis. Reconstitution of lymphopenic hosts with Nod2−/− CD4+ T cells or retina-specific autoreactive CD4+ T cells lacking Nod2 reveals a T cell-autonomous, Rip2-independent mechanism for Nod2 in uveitis. In naive animals, Nod2 operates downstream of TCR ligation to suppress activation of memory CD4+ T cells that associate with an autoreactive-like profile involving IL-17 and Ccr7. Interestingly, CD4+ T cells from two Blau syndrome patients show elevated IL-17 and increased CCR7. Our data define Nod2 as a T cell-intrinsic rheostat of Th17 immunity, and open new avenues for T cell-based therapies for Nod2-associated disorders such as Blau syndrome.

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T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis

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