Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production

Katrina L. Randall; Teresa Lambe; Andy Johnson; Bebhinn Treanor; Edyta Kucharska; Heather Domaschenz; Belinda Whittle; Lina E. Tze; Anselm Enders; Tanya L. Crockford; Tiphaine Bouriez-Jones; Duncan Alston; Jason G. Cyster; Michael J. Lenardo; Fabienne Mackay; Elissa K. Deenick; Stuart G. Tangye; Tyani D. Chan; Tahra Camidge; Robert Brink; Carola G. Vinuesa; Facundo D. Batista; Richard J. Cornall; Christopher C. Goodnow

doi:10.1038/ni.1820

Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production

Katrina L. Randall, Teresa Lambe, Andy Johnson, Bebhinn Treanor, Edyta Kucharska, Heather Domaschenz, Belinda Whittle, Lina E. Tze, Anselm Enders, Tanya L. Crockford, Tiphaine Bouriez-Jones, Duncan Alston, Jason G. Cyster, Michael J. Lenardo, Fabienne Mackay, Elissa K. Deenick, Stuart G. Tangye, Tyani D. Chan, Tahra Camidge, Robert BrinkCarola G. Vinuesa, Facundo D. Batista, Richard J. Cornall, Christopher C. Goodnow^*

^*Corresponding author for this work

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

224 Citations (Scopus)

Abstract

To identify genes and mechanisms involved in humoral immunity, we did a mouse genetic screen for mutations that do not affect the first wave of antibody to immunization but disrupt response maturation and persistence. The first two mutants identified had loss-of-function mutations in the gene encoding a previously obscure member of a family of Rho-Rac GTP-exchange factors, DOCK8. DOCK8-mutant B cells were unable to form marginal zone B cells or to persist in germinal centers and undergo affinity maturation. Dock8 mutations disrupted accumulation of the integrin ligand ICAM-1 in the B cell immunological synapse but did not alter other aspects of B cell antigen receptor signaling. Humoral immunodeficiency due to Dock8 mutation provides evidence that organization of the immunological synapse is critical for signaling the survival of B cell subsets required for long-lasting immunity.

Original language	English
Pages (from-to)	1283-1291
Number of pages	9
Journal	Nature Immunology
Volume	10
Issue number	12
DOIs	https://doi.org/10.1038/ni.1820
Publication status	Published - 2009

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Randall, K. L., Lambe, T., Johnson, A., Treanor, B., Kucharska, E., Domaschenz, H., Whittle, B., Tze, L. E., Enders, A., Crockford, T. L., Bouriez-Jones, T., Alston, D., Cyster, J. G., Lenardo, M. J., Mackay, F., Deenick, E. K., Tangye, S. G., Chan, T. D., Camidge, T., ... Goodnow, C. C. (2009). Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production. Nature Immunology, 10(12), 1283-1291. https://doi.org/10.1038/ni.1820

@article{af32777b02464beeba92ba752692bbe9,

title = "Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production",

abstract = "To identify genes and mechanisms involved in humoral immunity, we did a mouse genetic screen for mutations that do not affect the first wave of antibody to immunization but disrupt response maturation and persistence. The first two mutants identified had loss-of-function mutations in the gene encoding a previously obscure member of a family of Rho-Rac GTP-exchange factors, DOCK8. DOCK8-mutant B cells were unable to form marginal zone B cells or to persist in germinal centers and undergo affinity maturation. Dock8 mutations disrupted accumulation of the integrin ligand ICAM-1 in the B cell immunological synapse but did not alter other aspects of B cell antigen receptor signaling. Humoral immunodeficiency due to Dock8 mutation provides evidence that organization of the immunological synapse is critical for signaling the survival of B cell subsets required for long-lasting immunity.",

author = "Randall, {Katrina L.} and Teresa Lambe and Andy Johnson and Bebhinn Treanor and Edyta Kucharska and Heather Domaschenz and Belinda Whittle and Tze, {Lina E.} and Anselm Enders and Crockford, {Tanya L.} and Tiphaine Bouriez-Jones and Duncan Alston and Cyster, {Jason G.} and Lenardo, {Michael J.} and Fabienne Mackay and Deenick, {Elissa K.} and Tangye, {Stuart G.} and Chan, {Tyani D.} and Tahra Camidge and Robert Brink and Vinuesa, {Carola G.} and Batista, {Facundo D.} and Cornall, {Richard J.} and Goodnow, {Christopher C.}",

year = "2009",

doi = "10.1038/ni.1820",

language = "English",

volume = "10",

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journal = "Nature Immunology",

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Randall, KL, Lambe, T, Johnson, A, Treanor, B, Kucharska, E, Domaschenz, H, Whittle, B, Tze, LE, Enders, A, Crockford, TL, Bouriez-Jones, T, Alston, D, Cyster, JG, Lenardo, MJ, Mackay, F, Deenick, EK, Tangye, SG, Chan, TD, Camidge, T, Brink, R, Vinuesa, CG, Batista, FD, Cornall, RJ & Goodnow, CC 2009, 'Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production', Nature Immunology, vol. 10, no. 12, pp. 1283-1291. https://doi.org/10.1038/ni.1820

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T1 - Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production

AU - Randall, Katrina L.

AU - Lambe, Teresa

AU - Johnson, Andy

AU - Treanor, Bebhinn

AU - Kucharska, Edyta

AU - Domaschenz, Heather

AU - Whittle, Belinda

AU - Tze, Lina E.

AU - Enders, Anselm

AU - Crockford, Tanya L.

AU - Bouriez-Jones, Tiphaine

AU - Alston, Duncan

AU - Cyster, Jason G.

AU - Lenardo, Michael J.

AU - Mackay, Fabienne

AU - Deenick, Elissa K.

AU - Tangye, Stuart G.

AU - Chan, Tyani D.

AU - Camidge, Tahra

AU - Brink, Robert

AU - Vinuesa, Carola G.

AU - Batista, Facundo D.

AU - Cornall, Richard J.

AU - Goodnow, Christopher C.

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AB - To identify genes and mechanisms involved in humoral immunity, we did a mouse genetic screen for mutations that do not affect the first wave of antibody to immunization but disrupt response maturation and persistence. The first two mutants identified had loss-of-function mutations in the gene encoding a previously obscure member of a family of Rho-Rac GTP-exchange factors, DOCK8. DOCK8-mutant B cells were unable to form marginal zone B cells or to persist in germinal centers and undergo affinity maturation. Dock8 mutations disrupted accumulation of the integrin ligand ICAM-1 in the B cell immunological synapse but did not alter other aspects of B cell antigen receptor signaling. Humoral immunodeficiency due to Dock8 mutation provides evidence that organization of the immunological synapse is critical for signaling the survival of B cell subsets required for long-lasting immunity.

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SP - 1283

EP - 1291

JO - Nature Immunology

JF - Nature Immunology

IS - 12

ER -

Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production

Abstract

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