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

College of Medicine and Public Health

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

20 Citations (Scopus)

38 Downloads (Pure)

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
Article number	5406
Number of pages	16
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-18961-0
Publication status	Published - 1 Dec 2020

Keywords

Autoimmunity
NOD-like receptors
Signal transduction
T-helper 17 cells

Access to Document

10.1038/s41467-020-18961-0Licence: CC BY

Napier_TCell_P2020Final published version, 3.78 MBLicence: CC BY

Cite this

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

@article{ed25dc92020b4ed6a1d8d56d78a4539a,

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.",

keywords = "Autoimmunity, NOD-like receptors, Signal transduction, T-helper 17 cells",

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

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-18961-0",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature",

number = "1",

}

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

TY - JOUR

T1 - T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis

AU - Napier, Ruth J.

AU - Lee, Ellen J.

AU - Davey, Michael P.

AU - Vance, Emily E.

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.

PY - 2020/12/1

Y1 - 2020/12/1

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.

KW - Autoimmunity

KW - NOD-like receptors

KW - Signal transduction

KW - T-helper 17 cells

UR - http://www.scopus.com/inward/record.url?scp=85093959734&partnerID=8YFLogxK

UR - http://purl.org/au-research/grants/ARC/FT130101648

U2 - 10.1038/s41467-020-18961-0

DO - 10.1038/s41467-020-18961-0

M3 - Article

AN - SCOPUS:85093959734

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5406

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this