Akt1 and Akt2 promote peripheral B-cell maturation and survival

Abstract

Although the 3 isoforms of Akt regulate cell growth, proliferation, and survival in a wide variety of cell types, their role in B-cell development is unknown. We assessed B-cell maturation in the bone marrow (BM) and periphery in chimeras established with fetal liver progenitors lacking Akt1 and/or Akt2. We found that the gen- IntroductionIn adults, mature B cells derive from a series of precursors in the bone marrow (BM) and periphery. B-lineage committed pro-B cells in the BM undergo V-DJ recombination at the immunoglobulin (Ig) heavy chain locus, and cells possessing functional heavy chains are selected via the pre-B cell receptor (pre-BCR) to generate pre-B cells. 1 The majority of Ig light chain rearrangements occur in pre-B cells, and cells with productive light chain rearrangements yield immature B-cell receptor-positive (BCR ϩ ) B cells. 2 Newly formed BCR ϩ cells in the BM either die or mature further after entering peripheral lymphoid tissues such as the spleen. 3 One outcome of peripheral B-cell maturation is the selection of recently formed "transitional" B cells into functionally distinct B-cell subpopulations. Whereas the bulk of surviving transitional B cells yield follicular B cells, so named because of their enrichment in B cell-rich follicles in the spleen and lymph nodes, small numbers of transitional B cells differentiate into marginal zone (MZ) or B1 B cells, the main sources of antibody to T cell-independent bacterial pathogens. 4,5 The Akt family of serine/threonine kinases is expressed in 3 distinctly coded isoforms termed Akt-1, Akt-2, and Akt-3. 6 All 3 proteins share similar functions and structures, 7 and are known to enhance cellular metabolism and positively regulate cell survival and proliferation by activating numerous downstream biochemical pathways. 8 Activation of Akt requires phosphatidylinositol-3 kinase (PI-3K), a heterodimeric lipid kinase recruited to the plasma membrane upon ligation of a variety of surface receptors. 9 In B cells, PI-3K and Akt are activated upon ligation of a BCR coreceptor complex consisting of CD19, CD81, or CD21. [10][11][12] Interestingly, mice lacking CD19 or the catalytic subunit of PI-3K fail to develop MZ or B1 B cells, [13][14][15] suggesting that the CD19/ PI-3K pathway optimizes BCR-mediated peripheral B-cell maturation and selection. Consistent with this model, aggregation of the BCR leads to CD19-dependent phosphorylation and activation of Akt. 11 However, the CD19/PI-3K pathway activates several additional signaling pathways with important roles in BCR-mediated B-cell activation. Therefore, whether the Akt pathway plays an essential role in peripheral B-cell maturation and selection remains unclear.Recent observations show that Akt activity is required for early stages of T-cell development in the thymus. Specifically, thymocyte progenitors lacking Akt1 and Akt2 were unable to effectively transit the DN3 to double-positive transition, 16,17 which is characterized by a robust proliferative burst mediated by the pre-T cell receptor. 18 Beca...

Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical for B Cell Receptor Signaling in Transitional B Cells

“…Common phenotypic features of p85a-and p110d-deficient mice include an impairment of pro-B cell differentiation, a decrease of splenic B cell populations, and a deficiency of B1 B cells. In comparison, Akt1/2 double deficiency resulted in depletion of marginal zone and B1 B cells, but showed less pronounced effects on transitional and follicular B cells (64). However, Akt3 expression was still intact in these mice.…”

“…A significant depletion of marginal zone and B1 B cells is also a characteristic feature of SPPL2a 2/2 mice (13). In several of the above-mentioned models, the capability of the antiapoptotic protein Bcl-2 to rescue the respective B cell phenotypes upon transgenic overexpression has been evaluated (57,64,65). Although Bcl-2 expression was able to enhance survival of the knockout B cells, their failure to differentiate and to mature properly was not rescued accordingly, underlining the unique requirement of the individual pathways for B cell differentiation.…”

Protein kinase N1, a cell inhibitor of Akt kinase, has a central role in quality control of germinal center formation

“…Surprisingly, mature B cells were rescued in B-cell antigen receptor (BCR)-negative mice by ectopically expressing a constitutively active PI3K or specifically ablating B-cell PTEN expression (15). Moreover, ectopic Akt1 expression in mouse lymphocytes results in peripheral B and T cells (16), whereas bone marrow chimera mice lacking Akt1 and Akt2 in hematopoietic cells have substantially reduced marginal zone B and B1 cells, similar to PI3K-deficient mice (17). A human lacking the PI3K p85α subunit had a much earlier block in B-cell development than was evident in p85α-deficient mice (18).…”

Constitutive Akt1 signals attenuate B‐cell receptor signaling and proliferation, but enhance B‐cell migration and effector function

“…Genetic studies have shown that Akt1 and Akt2 are needed for the generation of MZ B cells and B1 B cells, but not of follicular B2 cells [12,13]. In addition, Akt2 suppresses the transcriptional activity of FoxO1, which inhibits Rag expression and V(D)J rearrangement in B-cell progenitors and, thereby, affects early B-cell maturation [14].…”