B cell-specific Deficiencies in mTOR Limit Germinal Center Formation and Humoral Immune Responses

Friday, November 08, 2013 — Poster Session IV
2:00 p.m. – 4:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NCI	IMMUNO-31

Authors

SL Zhang
D Tran
W DuBios
M Pruitt
S Hoover
RM Simpson
C Snapper
R Casellas
B Mock

Abstract

Generation of high-affinity antibodies in response to foreign antigens is essential for developing long-lasting immune responses; B cell maturation requires immunoglobulin (Ig) somatic hypermutation (SHM) and class-switch recombination (CSR) for high-affinity responses. Upon immunization with T-cell dependent antigens, knock-in (KI) mice hypomorphic for mTOR function had decreased ability to form germinal centers, develop high-affinity specific antibodies, and perform SHM/CSR. Hypomorphic mTOR mice also had a high mortality rate (40%) compared to WT (0%) littermates and had lower specific antibody titers when immunized and challenged with live bacteria. Mice with mTOR deleted in their B cell lineage (KO) also produced fewer splenic germinal centers and decreased high-affinity antibody responses. CSR rates were lower in mTOR KI and KO mice, and pharmacologic inhibition of mTOR in WT B cells resulted in decreased rates of ex vivo CSR. The activation-induced cytidine deaminase (AID), a protein essential for SHM and CSR, was lower in B cells from both KI and B-cell specific KO mice, and rescue experiments increasing AID expression in KI B cells restored CSR levels to those in wild-type B cells. Thus, mTOR plays an important immunoregulatory role, at least partially through AID signaling, in generating high affinity antibodies.