Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production.
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.
Randall
Katrina L
KL
John Curtin School of Medical Research and Australian Phenomics Facility, Australian National University, Australia.
Lambe
Teresa
T
Johnson
Andy L
AL
Johnson
Andy
A
Treanor
Bebhinn
B
Kucharska
Edyta
E
Domaschenz
Heather
H
Whittle
Belinda
B
Tze
Lina E
LE
Enders
Anselm
A
Crockford
Tanya L
TL
Bouriez-Jones
Tiphaine
T
Alston
Duncan
D
Cyster
Jason G
JG
Lenardo
Michael J
MJ
Mackay
Fabienne
F
Deenick
Elissa K
EK
Tangye
Stuart G
SG
Chan
Tyani D
TD
Camidge
Tahra
T
Brink
Robert
R
Vinuesa
Carola G
CG
Batista
Facundo D
FD
Cornall
Richard J
RJ
Goodnow
Christopher C
CC
D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D001483:Base Sequence; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D020836:Protein Structure, Quaternary; D016415:Sequence Alignment; D013569:Synapses / Q000276:immunology*
C545324:Dock8 protein, mouse; D020662:Guanine Nucleotide Exchange Factors