TY - JOUR
T1 - A forward genetic screen reveals roles for Nfkbid, Zeb1, and Ruvbl2 in humoral immunity
AU - Arnold, Carrie N.
AU - Pirie, Elaine
AU - Dosenovic, Pia
AU - McInerney, Gerald M.
AU - Xia, Yu
AU - Wang, Nathaniel
AU - Li, Xiaohong
AU - Siggs, Owen M.
AU - Karlsson Hedestam, Gunilla B.
AU - Beutler, Bruce
PY - 2012/7/31
Y1 - 2012/7/31
N2 - Using chemical germ-line mutagenesis, we screened mice for defects in the humoral immune response to a type II T-independent immunogen and an experimental alphavirus vector. A total of 26 mutations that impair humoral immunity were recovered, and 19 of these mutations have been positionally cloned. Among the phenovariants were bumble, cellophane, and Worker ascribed to mutations in Nfkbid, Zeb1, and Ruvbl2, respectively. We show that IκBNS, the nuclear IκB-like protein encoded by Nfkbid, is required for the development of marginal zone and peritoneal B-1 B cells and additionally required for extrafollicular antibody responses to T-independent and -dependent immunogens. Zeb1 is also required for marginal zone and peritoneal B-1 B-cell development as well as T-cell development, germinal center formation, and memory B-cell responses. Finally, Ruvbl2 is required for T-cell development and maximal T-dependent antibody responses. Collectively, the mutations that we identified give us insight into the points at which disruption of an antibody response can occur. All of the mutations identified to date directly affect lymphocyte development or function; none have an exclusive effect on cells of the innate immune system.
AB - Using chemical germ-line mutagenesis, we screened mice for defects in the humoral immune response to a type II T-independent immunogen and an experimental alphavirus vector. A total of 26 mutations that impair humoral immunity were recovered, and 19 of these mutations have been positionally cloned. Among the phenovariants were bumble, cellophane, and Worker ascribed to mutations in Nfkbid, Zeb1, and Ruvbl2, respectively. We show that IκBNS, the nuclear IκB-like protein encoded by Nfkbid, is required for the development of marginal zone and peritoneal B-1 B cells and additionally required for extrafollicular antibody responses to T-independent and -dependent immunogens. Zeb1 is also required for marginal zone and peritoneal B-1 B-cell development as well as T-cell development, germinal center formation, and memory B-cell responses. Finally, Ruvbl2 is required for T-cell development and maximal T-dependent antibody responses. Collectively, the mutations that we identified give us insight into the points at which disruption of an antibody response can occur. All of the mutations identified to date directly affect lymphocyte development or function; none have an exclusive effect on cells of the innate immune system.
UR - http://www.scopus.com/inward/record.url?scp=84864502473&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84864502473&partnerID=8YFLogxK
U2 - 10.1073/pnas.1209134109
DO - 10.1073/pnas.1209134109
M3 - Article
C2 - 22761313
AN - SCOPUS:84864502473
SN - 0027-8424
VL - 109
SP - 12286
EP - 12293
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 31
ER -