Distinct Activation Signals Determine whether IL-21 Induces B Cell Costimulation, Growth Arrest, or Bim-Dependent Apoptosis

Jin, Haoli; Carrió, Roberto; Yu, Aixin; Malek, Thomas R.

doi:10.4049/jimmunol.173.1.657

Cited by 239 publications

(306 citation statements)

References 45 publications

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“…Taken together with the other iMB cell features described above, we conclude that iMB cells are phenotypically and functionally equivalent to physiological B mem cells. 9 -12 , and facilitates proliferation of BCR-/ CD40-stimulated B cells 14,44 . Primary culture with IL-21 on 40LB feeder cells for 4 days resulted in 25-fold less proliferation of B cells than in the cultures with IL-4, with less frequent or little switching to IgG1 and IgE, respectively.…”

Section: Generation Of B Mem Cells From Igb Cells In Vivomentioning

confidence: 99%

In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo

et al. 2011

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In response to T cell-dependent antigens, B cells proliferate extensively to form germinal centres (GC), and then differentiate into memory B (B mem ) cells or long-lived plasma cells (LLPCs) by largely unknown mechanisms. Here we show a new culture system in which mouse na ï ve B cells undergo massive expansion and isotype switching, and generate GC-phenotype B (iGB) cells. The iGB cells expressing IgG1 or IgM / D, but not IgE, differentiate into B mem cells in vivo after adoptive transfer and can elicit rapid immune responses with the help of cognate T cells. Secondary culture with IL-21 maintains the proliferation of the iGB cells, while shifting their in vivo developmental fate from B mem cells to LLPCs, an outcome that can be reversed by withdrawal of IL-21 in tertiary cultures. Thus, this system enables in vitro manipulation of B-cell fate, into either B mem cells or LLPCs, and will facilitate dissection of GC-B cell differentiation programs.

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Section: Generation Of B Mem Cells From Igb Cells In Vivomentioning

confidence: 99%

In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo

et al. 2011

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“…In both T and B cells, IL-21R is increased by ligation of both the antigen receptor and the Toll-like receptors in B cells. 19 Expression of IL-21R is downregulated by IFN-in both T and natural killer cells, 20 whereas in T cells, IL-21 promotes the expression of its own receptor. 21 Functionally, IL-21 augments the proliferation and cytokine profile of CD4 + and CD8 T lymphocytes.…”

Section: The Additional Role Of Il-21 In Mediating Th1 Immune Responsmentioning

confidence: 99%

IL-21 comes of age as a regulator of effector T cells in the gut

2008

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In healthy individuals, antigens from the gut lumen are tolerated by the mucosal immune system. However, a loss of tolerance toward the bacterial microflora probably causes inflammatory bowel disease (IBD), Crohn ' s disease (CD) and ulcerative colitis. The abnormal activation of the immune system in the gut of IBD patients is characterized by a cascade of cellular events orchestrated by cytokine cross talk between immune and non-immune cells. Interleukin (IL)-21, the newest member of the common -chain-dependent cytokine family, is a key component of the inflammatory cascade in the gut. It is highly expressed in CD and sustains the ongoing T helper type 1 (Th1)-mediated immune response. IL-21 is essential for the differentiation of Th17 cells. IL-21 is also involved in recruiting T cells to the inflamed gut and eliciting the secretion of matrix-degrading enzymes by gut fibroblasts. Overall, there is now sufficient evidence to suggest that targeting IL-21 will be of therapeutic benefit in IBD.

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“…Indeed, murine B cells and human B-chronic lymphocytic leukemic (B-CLL) cells up-regulate expression of IL-21R following exposure to LPS (33) and CD40L (54), respectively. Thus, expression of IL-21R was assessed following stimulation with CD40L.…”

Section: Expression Of Il-21r Increases Following Activationmentioning

confidence: 99%

Kinetics of Human B Cell Behavior and Amplification of Proliferative Responses following Stimulation with IL-21

Good

Bryant

Tangye

2006

The Journal of Immunology

247

237

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Although recent studies indicated that IL-21 is an important regulator of human B cell activation, detailed comparison of the effects of IL-21 on distinct B cell subsets have not been performed. Our studies revealed that IL-21R is expressed by naive and germinal center B cells, but not memory or plasma cells. IL-21R was increased on naive and memory B cells following in vitro activation. Investigation into the kinetics and magnitude of responses of human B cells to IL-21 revealed that IL-21 potently augmented proliferation of CD40L-stimulated neonatal, splenic naive, and memory and tonsil germinal center B cells. This response exceeded that induced by IL-4, IL-10, and IL-13, cytokines that also induce B cell proliferation. Remarkably, CD40L/IL-21-stimulated naive B cells underwent the same number of divisions as memory cells and exhibited a greater enhancement in their response compared with CD40L alone than memory B cells. Therefore, IL-21 is a powerful growth factor for naive B cells. This may result from the higher expression of IL-21R on naive, compared with memory, B cells. Stimulation of human B cells with CD40L/IL-21 also induced IL-10 production and activation of STAT3. We propose that IL-21 may have therapeutic application in conditions of immunodeficiency where it could expand naive B cells, the predominant B cell subset in such patients. Conversely, because IL-21 is increased in murine models of lupus, dysregulated IL-21 production may contribute to perturbed B cell homeostasis observed in systemic lupus erythematosus. Thus, antagonizing IL-21 may be a novel strategy for treating Ab-mediated autoimmune diseases.

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Distinct Activation Signals Determine whether IL-21 Induces B Cell Costimulation, Growth Arrest, or Bim-Dependent Apoptosis

Cited by 239 publications

References 45 publications

In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo

In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo

IL-21 comes of age as a regulator of effector T cells in the gut

Kinetics of Human B Cell Behavior and Amplification of Proliferative Responses following Stimulation with IL-21

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