Receptor crosslinking of T-cell hybridomas induces cell activation followed by apoptosis. This activation-induced cell death requires de novo synthesis of RNA and proteins, but the actual gene products that provide the death signal have not been identified. We show here that receptor crosslinking induces Fas ligand and upregulates Fas, and that the ensuing engagement of Fas by Fas ligand activates the cell-death programme. Cell death, but not activation, can be selectively prevented by a soluble Fas-immunoglobulin fusion protein. Thus, Fas and Fas ligand are the death-gene products, and their interaction accounts for the molecular mechanism of activation-induced T-cell death.
IL-21 is a type I cytokine whose receptor is expressed on T, B, and NK cells. Within the B cell lineage, IL-21 regulates IgG1 production and cooperates with IL-4 for the production of multiple Ab classes in vivo. Using IL-21-transgenic mice and hydrodynamics-based gene delivery of IL-21 plasmid DNA into wild-type mice as well as in vitro studies, we demonstrate that although IL-21 induces death of resting B cells, it promotes differentiation of B cells into postswitch and plasma cells. Thus, IL-21 differentially influences B cell fate depending on the signaling context, explaining how IL-21 can be proapoptotic for B cells in vitro yet critical for Ag-specific Ig production in vivo. Moreover, we demonstrate that IL-21 unexpectedly induces expression of both Blimp-1 and Bcl-6, indicating mechanisms as to how IL-21 can serve as a complex regulator of B cell maturation and terminal differentiation. Finally, BXSB-Yaa mice, which develop a systemic lupus erythematosus-like disease, have greatly elevated IL-21, suggesting a role for IL-21 in the development of autoimmune disease.
IL-21 is a type I cytokine that influences the function of T cells, NK cells, and B cells. In this study, we report that IL-21 plays a major role in stimulating the differentiation of human B cells. When human B cells were stimulated through the BCR, IL-21 induced minimal proliferation, IgD down-modulation, and small numbers of plasma cells. In contrast, after CD40 engagement, IL-21 induced extensive proliferation, class switch recombination (CSR), and plasma cell differentiation. Upon cross-linking both BCR and CD40, IL-21 induced the largest numbers of plasma cells. IL-21 drove both postswitch memory cells as well as poorly responsive naive cord blood B cells to differentiate into plasma cells. The effect of IL-21 was more potent than the combination of IL-2 and IL-10, especially when responsiveness of cord blood B cells was examined. IL-21 costimulation potently induced the expression of both B lymphocyte-induced maturation protein-1 (BLIMP-1) and activation-induced cytidine deaminase as well as the production of large amounts of IgG from B cells. Despite the induction of activation-induced cytidine deaminase and CSR, IL-21 did not induce somatic hypermutation. Finally, IL-2 enhanced the effects of IL-21, whereas IL-4 inhibited IL-21-induced plasma cell differentiation. Taken together, our data show that IL-21 plays a central role in CSR and plasma cell differentiation during T cell-dependent B cell responses.
Although the aetiology of systemic lupus erythematosus (SLE) is unclear, dysregulated B cell responses have been implicated. Here we show that an unusual CD11chiT-bet+ B cell subset, with a unique expression profile including chemokine receptors consistent with migration to target tissues, is expanded in SLE patients, present in nephrotic kidney, enriched for autoreactive specificities and correlates with defined clinical manifestations. IL-21 can potently induce CD11chiT-bet+ B cells and promote the differentiation of these cells into Ig-secreting autoreactive plasma cells. While murine studies have identified a role for T-bet-expressing B cells in autoimmunity, this study describes and exemplifies the importance of CD11chiT-bet+ B cells in human SLE.
IntroductionPrimary B-cell development takes place in the bone marrow, where immature B cells must generate a functional B-cell receptor (BCR) and overcome negative selection induced by reactivity with autoantigens. [1][2][3] In mice, approximately 10% of immature B cells survive these processes and emerge from the bone marrow expressing surface immunoglobulin M (IgM) and IgD. 4 These immature "transitional" B cells transit to the spleen where they mature to become responsive to BCR-mediated signaling. [5][6][7][8][9] Only a fraction of cells survive this process of secondary (peripheral) B-cell development. 10,11 Cell surface markers have been identified that enable different stages of peripheral B-cell maturation to be characterized. In mice, heat-stable antigen (HSA, CD24) was used to distinguish immature (CD24 hi ) from mature (CD24 lo ) splenic B cells. 12 Additional cell surface markers have been used to subdivide murine splenic transitional B cells into 2 distinct populations; transitional type 1 (T1; CD24 hi , CD21 lo , CD23 lo , IgM hi , IgD lo ) and transitional T2 (CD24 hi , CD21 hi , CD23 hi , IgM hi , IgD hi ). 5 An alternative classification defines 3 types of transitional B cells using reactivity to a C1q receptor related protein to identify immature B cells and CD23 and IgM to distinguish T1 (CD23 Ϫ , IgM hi ), T2 (CD23 ϩ , IgM hi ), and T3 (CD23 ϩ , IgM lo ). 7,11 Importantly, T1 B cells are found in the bone marrow, blood, and spleen, but not lymph nodes, whereas T2 B cells are restricted to the spleen. Moreover, in vivo transfer experiments demonstrate that T1 cells give rise to T2 cells and B cells with a mature phenotype. 5,8 Most studies demonstrate that T2 cells increase in size, up-regulate survival signals, proliferate, and differentiate upon BCR ligation, whereas T1 cells die. 5,9,13 Finally, B-cell activation factor member of the tumor necrosis factor (TNF) family (BAFF) plays an integral role in the survival and maturation of murine B cells, although it remains unclear if it affects T1 or T2 B cells. 14 Most of the knowledge on primary and peripheral B-cell development is derived from mice. Many aspects of development in bone marrow appear similar in humans; however, our understanding of peripheral B-cell development is remarkably limited. As a first step in a systematic approach to address this issue, we have identified and characterized the phenotype and function of human transitional B cells from peripheral blood. Human transitional T1 B cells show some similarities, but some significant differences compared with their counterparts in murine spleen. Moreover, the presence of circulating B cells that resemble T2 B cells with respect to both phenotype and function suggests that human B-cell maturation may not be restricted to the spleen. Finally, we found increased proportions of T1 B cells in patients with systemic lupus erythematosus (SLE) that reflected peripheral lymphopenia rather than abnormalities in bone marrow production or selection in these patients with autoimmune disease...
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