TY - JOUR
T1 - Independent Roles of Switching and Hypermutation in the Development and Persistence of B Lymphocyte Memory
AU - Gitlin, Alexander D.
AU - von Boehmer, Lotta
AU - Gazumyan, Anna
AU - Shulman, Ziv
AU - Oliveira, Thiago Y.
AU - Nussenzweig, Michel C.
N1 - We thank T. Eisenreich and S. Hinklein for help with mouse colony management; S. Bournazos for reagents; M.K. Jenkins, J.J. Taylor, and K.A. Pape for generous advice; E.S. Gitlin, H. Mouquet, D. Mucida, G.D. Victora, and C.T. Mayer for discussion and advice; D.F. Robbiani, P.C. Rommel, A. Weiss, and J. Zikherman for mice; J. Golijanin, S. Ackerman, and K. Yao for technical help; B. Zhang and C. Zhao and the Rockefeller University Genomics Resource Center for assistance with high-throughput sequencing; K. Velinzon and N. Thomas for assistance with cell sorting; and all members of the Nussenzweig laboratory for discussion. Supported by NIH Medical Scientist Training Program grant T32GM07739 and National Institute of Allergy and Infectious Diseases, NIH, grant 1F30AI109903-01 (A.D.G.); grant UL1 TR000043 from the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award program (L.v.B.); NIH grants AI037526-19 and AI072529-06 (M.C.N.); and the NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) 1UM1 AI100663-01 (M.C.N). Z.S. is a Human Frontiers of Science Program fellow (reference LT000340/2011-L). M.C.N. is an HHMI investigator.
PY - 2016/4/19
Y1 - 2016/4/19
N2 - Somatic hypermutation (SHM) and class-switch recombination (CSR) increase the affinity and diversify the effector functions of antibodies during immune responses. Although SHM and CSR are fundamentally different, their independent roles in regulating B cell fate have been difficult to uncouple because a single enzyme, activation-induced cytidine deaminase (encoded by Aicda), initiates both reactions. Here, we used a combination of Aicda and antibody mutant alleles that separate the effects of CSR and SHM on polyclonal immune responses. We found that class-switching to IgG1 biased the fate choice made by B cells, favoring the plasma cell over memory cell fate without significantly affecting clonal expansion in the germinal center (GC). In contrast, SHM reduced the longevity of memory B cells by creating polyreactive specificities that were selected against over time. Our data define the independent contributions of SHM and CSR to the generation and persistence of memory in the antibody system.
AB - Somatic hypermutation (SHM) and class-switch recombination (CSR) increase the affinity and diversify the effector functions of antibodies during immune responses. Although SHM and CSR are fundamentally different, their independent roles in regulating B cell fate have been difficult to uncouple because a single enzyme, activation-induced cytidine deaminase (encoded by Aicda), initiates both reactions. Here, we used a combination of Aicda and antibody mutant alleles that separate the effects of CSR and SHM on polyclonal immune responses. We found that class-switching to IgG1 biased the fate choice made by B cells, favoring the plasma cell over memory cell fate without significantly affecting clonal expansion in the germinal center (GC). In contrast, SHM reduced the longevity of memory B cells by creating polyreactive specificities that were selected against over time. Our data define the independent contributions of SHM and CSR to the generation and persistence of memory in the antibody system.
UR - http://www.scopus.com/inward/record.url?scp=84961119572&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2016.01.011
DO - 10.1016/j.immuni.2016.01.011
M3 - مقالة
SN - 1074-7613
VL - 44
SP - 769
EP - 781
JO - Immunity
JF - Immunity
IS - 4
ER -