B Cell–Specific Deficiencies in mTOR Limit Humoral Immune Responses

Abstract

Generation of high-affinity Abs in response to Ags/infectious agents is essential for developing long-lasting immune responses. B cell maturation and Ab responses to Ag stimulation require Ig somatic hypermutation (SHM) and class-switch recombination (CSR) for high-affinity responses. Upon immunization with either the model Ag 4-hydroxy-3-nitrophenylacetyl hapten (NP) conjugated to chicken γ globulin lysine (NP-CGG) or heat-killed Streptococcus pneumoniae capsular type 14 protein (Pn14), knock-in (KI) mice hypomorphic for mTOR function had a decreased ability to form germinal centers, develop high-affinity anti-NP–specific or anti-Pn14–specific Abs, and perform SHM/CSR. Hypomorphic mTOR mice also had a high mortality (40%) compared with wild-type (WT) (0%) littermates and had lower pneumococcal surface protein A–specific Ab titers when immunized and challenged with live S. pneumoniae infection. Mice with mTOR deleted in their B cell lineage (knockout [KO]) also produced fewer splenic germinal centers and decreased high-affinity Ab responses to NP-CGG than did their WT littermates. 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. RNA and protein levels of activation-induced cytidine deaminase (AID), a protein essential for SHM and CSR, were lower in B cells from both KI and B cell–specific KO mice, concomitant with increases in phosphorylated AKT and FOXO1. Rescue experiments increasing AID expression in KI B cells restored CSR levels to those in WT B cells. Thus, mTOR plays an important immunoregulatory role in the germinal center, at least partially through AID signaling, in generating high-affinity Abs.

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

“…69 To determine whether these effects were caused by a direct mTOR blockade in the B cells or only reflected T cell deficiency, the same group examined the humoral responses in mTOR conditional B cell knockout mice. 71 Mice with mTOR deleted in their B cell lineage produced fewer splenic germinal centers and also, exhibited a decrease in switched highaffinity antibody responses in contrast to their wild-type littermates. 71 The fact that mTOR inhibitors are able to prevent the in vitro production of Ig with equal efficiency when human B cells are cultured with preactivated or not preactivated T cells further shows that mTOR inhibitors, in contrast with CNIs, have a direct effect on B cells.…”

“…71 Mice with mTOR deleted in their B cell lineage produced fewer splenic germinal centers and also, exhibited a decrease in switched highaffinity antibody responses in contrast to their wild-type littermates. 71 The fact that mTOR inhibitors are able to prevent the in vitro production of Ig with equal efficiency when human B cells are cultured with preactivated or not preactivated T cells further shows that mTOR inhibitors, in contrast with CNIs, have a direct effect on B cells. 65,72 This concept is also validated by the results of a recent study that compared the effects of CNI and mTOR inhibitors on B cells from healthy volunteers.…”

mTOR has distinct functions in generating versus sustaining humoral immunity

“…One recent report illustrated a clear role for RICTOR and mTORC2 signaling in the development of naive B cell pools (26), and other work indicates that rapamycin inhibits or ablates ongoing GC responses, thus attenuating the generation of high-affinity antibodies (27,28). Additionally, B cell proliferation and class switch recombination (CSR) are compromised in mTOR hypomorphs or by conditional Mtor deletion in naive B cells (28), although the latter strategy necessarily affects both mTORC1 and mTORC2 signaling. Similarly, rapamycin compromises in vitro B cell proliferation and protein synthesis, and Raptor deletion in transitional B cells suppresses CSR and plasmablast generation (29,30).…”

mTOR Promotes Antiviral Humoral Immunity by Differentially Regulating CD4 Helper T Cell and B Cell Responses

“…However, considering that most successful vaccines confer protective immunity by inducing antibody responses (12), it is critical to understand whether and how mTOR regulates the generation of antigen-specific antibodies. Recent studies examined the role of mTOR in B cells and found that mTOR signals are required for production of high-affinity antibodies (13)(14)(15). These studies focused on B cell responses (13)(14)(15), but the interplay between CD4 T cells and B cells remains unclear in cases where mTOR signals are inhibited in both CD4 T cells and B cells in vivo, such as by rapamycin treatment.…”