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Shown are representative fluorescence-activated cell sorter FACS profiles in the gates as indicated in the above panels right. C Ratios of CD No defect was apparent 2 weeks after the first tamoxifen injection data not shown.
Although Rictor deletion impairs thymic production of new T cells, 29 B-cell maintenance is T cell independent. Together, these results indicate that Rictor mediates maintenance of mature B cells.
Effect of acute Rictor deletion on B lymphoid cells. C Representative FACS profiles with frequencies of the indicated subsets in the viable lymphoid gates of the spleen or further gates as indicated in the above panels. Thus, this protein assists survival signaling in B cells. Impaired survival, proliferation, and persistence of Rictor-deficient B cells.
C Increased apoptosis of Rictor -deficient B cells. D Competitive homeostasis of mature B cells. Mice were then treated with tamoxifen and were analyzed by flow cytometry 4 weeks after the adoptive transfer. E Homeostatic proliferation of Rictor-deficient B cells. Shown is 1 result representative of those in 3 independent experiments, each consisting of 4 mice of each genotype.
Consistent with impaired Akt function at a nuclear target after Rictor depletion, much less phosphorylation of FoxO1 was observed Figure 5A. Shown are signal images for the indicated antibody in 1 of 3 independent experiments with comparable results. To explore the signaling defects in relation to B-cell survival, we analyzed expression of proapoptotic and antiapoptotic genes in B cells lacking Rictor.
These data indicate that Rictor assists in setting an appropriate balance of prosurvival and proapoptotic gene expression in B cells. Rictor regulates induction of prosurvival genes and suppression of proapoptotic genes.
A Relative expression of Bcl2 family genes ex vivo. Mature AA4. Antibody responses depend on the clonal expansion of antigen-reactive B cells, germinal center formation, and the differentiation and maintenance of plasma cells. This impact was most striking for high-affinity antibodies of class-switched isotypes.
Moreover, germinal centers in the spleens of immunized Rictor-deficient mice were sparse and smaller supplemental Figure 4C. Comparison of these defects to our previous findings with depletion of Rictor in mature T cells 26 and the numbers of FO B-phenotype cells suggested that Rictor also acts within B cells in antibody responses. High-affinity and class-switched antibodies are promoted by the germinal center reaction. Despite suitable T-cell help, frequencies of germinal center-phenotype B cells were reduced when Rictor-depleted B cells were used Figure 7D.
Thus, we conclude that Rictor within B lineage cells promoted population expansion and the antibody response. Overall, we propose that Rictor promotes the development of the preimmune B-cell populations followed by survival during and after clonal expansion. B-cell—intrinsic role of Rictor in antibody responses. Sera of these recipient mice were analyzed 3 weeks after immunization with NP-conjugated ovalbumin. Our data show that development, homeostasis, and immune function of mature B cells depend on Rictor, a protein central to mTORC2.
These defects, together with lower cell-cycling efficiency, suggest that B-cell—intrinsic contributions of mTORC2 to survival signaling and clonal expansion are major elements in the defective antibody responses.
Intriguingly, TLR4-driven B-cell proliferation and in vitro antibody production exhibited less impact of Rictor deficiency Figure 4F ; supplemental Figure 6 , suggesting that antigen-driven, BCR-initiated signals may depend more stringently on Rictor than TLR-initiated processes. It is revealing to integrate these findings with other aspects of PI3K signaling. Strikingly, the impact of Rictor on maturation appeared nearly as substantial as that of Akt 1, 2. Akt is catalytically active after activation loop phosphorylation by PDK1, but its activity and the persistence of Tphosphorylation are increased by phosphorylation of the conserved HM S of Akt.
The Akt3 isoform may be sufficiently functional in B lineage cells that the Akt phenotype was only partially penetrant, or the biochemical dose-response curve for Akt may require a level of catalytic activity not achieved without HM phosphorylation. An intriguing possibility is that phosphorylation and structural rearrangement of the Akt HM promote functional targeting of biologically important substrates. FoxO1 deletion early in B lineage development caused blocks at pro- and pre-B—cell stages attributed to a failure to express RAG and the IL-7 receptor.
Recent findings with conditional Pten deletion show that the PI3K pathway affects the fetal blood progenitors very differently from stem cells of the adult marrow. Another striking phenotype observed in Rictor-deficient mice was a defect of MZ B cells, which were much more sensitive to acute deletion of Rictor than FO B cells. Although PI3K is activated in a myriad of ways, it is intriguing that Notch 2 signaling both activates this lipid kinase and promotes MZ B-cell development, 50 because mTORC2 relays Notch signals in pre-T—cell differentiation and expansion.
The online version of this article contains a data supplement. The publication costs of this article were defrayed in part by page charge payment. Contribution: K. The current address for K.
Conflict-of-interest disclosure: The authors declare no competing financial interests. Prepublished online Aug Thomas , 4 Robert C. Rickert , 2 and Mark Boothby 1, 4. James W. Robert C. Author information Article notes Copyright and License information Disclaimer. Corresponding author. Received Jan 7; Accepted Aug This article has been cited by other articles in PMC. Rictor regulates survival of B cells and their balance of proapoptotic vs antiapoptotic gene expression. Introduction Humoral immunity relies on suitable pools of mature B-cell subsets, and their capacity for clonal expansion and differentiation into antibody-secreting cells.
Methods Detailed Methods are outlined in the supplemental Materials. Immunohistochemistry, B-cell isolation, and flow cytometry Immunohistochemistry was performed on frozen sections of spleens as described. Western blotting; measurements of RNA Cell lysates were analyzed by immunoblotting. Open in a separate window. Figure 1. Figure 2. Figure 3.
Figure 4. Figure 5. Figure 6. B-cell—intrinsic Rictor contribution to antibody responses Antibody responses depend on the clonal expansion of antigen-reactive B cells, germinal center formation, and the differentiation and maintenance of plasma cells. Figure 7. Footnotes The online version of this article contains a data supplement.
Authorship Contribution: K. References 1. B cell signaling and fate decision. Annu Rev Immunol. Schlissel MS. Regulating antigen-receptor gene assembly. Nat Rev Immunol. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Clonal anergy: persistence in tolerant mice of antigen-binding B lymphocytes incapable of responding to antigen or mitogen. Shlomchik MJ, Weisel F. Germinal center selection and the development of memory B and plasma cells.
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