Kirsten Fairfax

FcγRIIb controls bone marrow plasma cell persistence and apoptosis

The survival of long-lived plasma cells, which produce most serum immunoglobulin, is central to humoral immunity. We found here that the inhibitory Fc receptor FcγRIIb was expressed on plasma cells and controlled their persistence in the bone marrow. Crosslinking FcγRIIb induced apoptosis of plasma cells, which we propose contributes to the control of their homeostasis and suggests a method for therapeutic deletion. Plasma cells from mice prone to systemic lupus erythematosus did not express FcγRIIb and were protected from apoptosis. Human plasmablasts expressed FcγRIIb and were killed by crosslinking, as were FcγRIIb-expressing myeloma cells. Our results suggest that FcγRIIb controls bone marrow plasma cell persistence and that defects in it may contribute to autoantibody production.

NK Cell Maturation and Peripheral Homeostasis Is Associated with KLRG1 Up-Regulation

NK cells are important for the clearance of tumors, parasites, and virus-infected cells. Thus, factors that control NK cell numbers and function are critical for the innate immune response. A subset of NK cells express the inhibitory killer cell lectin-like receptor G1 (KLRG1). In this study, we identify that KLRG1 expression is acquired during periods of NK cell division such as development and homeostatic proliferation. KLRG1+ NK cells are mature in phenotype, and we show for the first time that these cells have a slower in vivo turnover rate, reduced proliferative response to IL-15, and poorer homeostatic expansion potential compared with mature NK cells lacking KLRG1. Transfer into lymphopenic recipients indicate that KLRG1− NK cells are precursors of KLRG1+ NK cells and KLRG1 expression accumulates following cell division. Furthermore, KLRG1+ NK cells represent a significantly greater proportion of NK cells in mice with enhanced NK cell numbers such as Cd45−/− mice. These data indicate that NK cells acquire KLRG1 on their surface during development, and this expression correlates with functional distinctions from other peripheral NK cells in vivo.

The BAFF/APRIL system: Emerging functions beyond B cell biology and autoimmunity

Abstract The BAFF system plays a key role in the development of autoimmunity, especially in systemic lupus erythematosus (SLE). This often leads to the assumption that BAFF is mostly a B cell factor with a specific role in autoimmunity. Focus on BAFF and autoimmunity, driven by pharmaceutical successes with the recent approval of a novel targeted therapy Belimumab, has relegated other potential roles of BAFF to the background. Far from being SLE-specific, the BAFF system has a much broader relevance in infection, cancer and allergy. In this review, we provide the latest views on additional roles of the BAFF system in health and diseases, as well as an update on BAFF and autoimmunity, with particular focus on current clinical trials.

Plasma cell development: from B-cell subsets to long-term survival niches.

Recent advances in the identification of mouse plasma cells have enabled a more detailed assessment of their development and maintenance to be undertaken. Insertion of the gene encoding green fluorescent protein into the Blimp1 locus has allowed measurement of the efficiency and kinetics with which subsets of mature B cells generate antibody-secreting cells (ASCs) after culture with a series of mitogens, with and without co-stimulation. In vivo identification of plasma cells has allowed their phenotype to be defined and changes in their frequency as a result of aging and immunisation to be monitored. This new approach has allowed also a more precise definition of the genetic program activated in plasma cell differentiation. In this review we cover these aspects of plasma cell development with a particular emphasis on the B-cell subsets giving rise to the plasma cells and to their maintenance once formed.

Mcl-1 is essential for the survival of plasma cells

The long-term survival of plasma cells is entirely dependent on signals derived from their environment. These extrinsic factors presumably induce and sustain the expression of antiapoptotic proteins of the Bcl-2 family. It is uncertain whether there is specificity among Bcl-2 family members in the survival of plasma cells and whether their expression is linked to specific extrinsic factors. We found here that deletion of the gene encoding the antiapoptotic protein Mcl-1 in plasma cells resulted in rapid depletion of this population in vivo. Furthermore, we found that the receptor BCMA was needed to establish high expression of Mcl-1 in bone marrow but not spleen plasma cells and that establishing this survival pathway preceded the component of plasma cell differentiation that depends on the transcriptional repressor Blimp-1. Our results identify a critical role for Mcl-1 in the maintenance of plasma cells.

Different kinetics of blimp-1 induction in B cell subsets revealed by reporter gene.

The transcriptional repressor Blimp-1 (B lymphocyte-induced maturation protein 1) has been described as a “master regulator” of B cell differentiation into Ab-secreting cells (ASCs). Although there is mounting evidence for the importance and necessity of Blimp-1 in plasma cell development, there is uncertainty as to the role it plays in B cell differentiation of B cell subsets and the way in which it may interact with other transcription factors such as Pax5 and Bcl6 during ASC differentiation. Using a mouse expressing GFP under the control of the Blimp-1 regulatory elements (Blimp-1GFP/+), we examined the kinetics of Blimp-1 up-regulation in purified B cell subsets following activation. B1 cells showed the most rapid and pronounced up-regulation of Blimp-1 in response to the mitogens tested, followed by marginal zone B cells and then conventional B2 cells. Interestingly, only B1 cells substantially up-regulated Blimp-1 expression in response to CpG. B1 cells secreted negligible Ig upon isolation but were able to up-regulate Blimp-1 and initiate Ig secretion within 28 h of stimulation. Also of interest, B1 cells have a transcriptional factor profile that is intermediate between a naive B cell and an ASC, indicative of the semiactivated state of B1 cells. Transferred naive Blimp-1GFP/+ B1 and B2 cells both gave rise to ASCs in the bone marrow, suggesting no intrinsic barriers to B1 cell entry into the long-lived ASC compartment.

BLIMP1 guides the fate of effector B and T cells

B-lymphocyte-induced maturation protein 1 (BLIMP1) is a transcriptional repressor, and its importance in controlling the terminal differentiation of antibody-secreting cells (ASCs) is well established. However, as we discuss in this Progress article, it has now become evident that the ASC programme consists of a discrete BLIMP1-independent initiation phase, followed by a second step in which BLIMP1 is absolutely required for the differentiation of fully mature ASCs. In addition, an important role for BLIMP1 in maintaining the homeostasis of effector T cells is emerging, suggesting intriguing parallels between the control of effector-cell fates in both B and T cells.

Individual and overlapping roles of BH3-only proteins Bim and Bad in apoptosis of lymphocytes and platelets and in suppression of thymic lymphoma development

BH3-only proteins, such as Bim and Bad, contribute to tissue homeostasis by initiating apoptosis in a cell type- and stimulus-specific manner. Loss of Bim provokes lymphocyte accumulation in vivo and renders lymphocytes more resistant to diverse apoptotic stimuli and Bad has been implicated in the apoptosis of haematopoietic cells upon cytokine deprivation. To investigate whether their biological roles in apoptosis overlap, we generated mice lacking both Bim and Bad and compared their haematopoietic phenotype with that of the single-knockout and wild-type (wt) animals. Unexpectedly, bad−/− mice had excess platelets due to prolonged platelet life-span. The bim−/−bad−/− mice were anatomically normal and fertile. Their haematopoietic phenotype resembled that of bim−/− mice but lymphocytes were slightly more elevated in their lymph nodes. Although resting B and T lymphocytes from bim−/−bad−/− and bim−/− animals displayed similar resistance to diverse apoptotic stimuli, mitogen activated bim−/−bad−/− B cells were more refractory to cytokine deprivation. Moreover, combined loss of Bim and Bad-enhanced survival of thymocytes after DNA damage and accelerated development of γ-irradiation-induced thymic lymphoma. Unexpectedly, their cooperation in the thymus depended upon thymocyte–stromal interaction. Collectively, these results show that Bim and Bad can cooperate in the apoptosis of thymocytes and activated B lymphocytes and in the suppression of thymic lymphoma development.

The RNA-binding protein HuR is essential for the B cell antibody response

Post-transcriptional regulation of mRNA by the RNA-binding protein HuR (encoded by Elavl1) is required in B cells for the germinal center reaction and for the production of class-switched antibodies in response to thymus-independent antigens. Transcriptome-wide examination of RNA isoforms and their abundance and translation in HuR-deficient B cells, together with direct measurements of HuR-RNA interactions, revealed that HuR-dependent splicing of mRNA affected hundreds of transcripts, including that encoding dihydrolipoamide S-succinyltransferase (Dlst), a subunit of the 2-oxoglutarate dehydrogenase (α-KGDH) complex. In the absence of HuR, defective mitochondrial metabolism resulted in large amounts of reactive oxygen species and B cell death. Our study shows how post-transcriptional processes control the balance of energy metabolism required for the proliferation and differentiation of B cells.

Signaling Pathways in T Follicular Helper Cells

Th cell functional subsets have unique transcriptional programs that form the molecular basis for T cell differentiation and functions. T follicular helper (TFH) cells have emerged as the main providers of T cell help to B cells during the germinal center (GC) reaction, where B cells undergo selection events through competition for Ag and for access to GC T cell-mediated prosurvival and differentiation signals. Because T cell help is one limiting factor for GC B cells, the molecular mechanisms controlling TFH cell abundance and functionality are central to the GC reaction and generation of long-term humoral immunity. Two signaling pathways are absolutely critical for TFH cells: phosphoinositide-3 kinase pathway and the signaling lymphocyte activation molecule-associated protein. In this review, the molecular mechanisms constituting the signaling network in TFH cells will be explored.