Kinetics of human B cell behavior and amplification of proliferative responses following stimulation with IL-21.
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.
Good
Kim L
KL
Centenary Institute of Cancer Medicine and Cell Biology, New South Wales, Australia.
Bryant
Vanessa L
VL
Tangye
Stuart G
SG
D001402:B-Lymphocytes / Q000737:chemistry / Q000187:drug effects*; D023201:CD40 Ligand / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D016207:Cytokines / Q000494:pharmacology; D018858:Germinal Center / Q000166:cytology; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D007378:Interleukins / Q000494:pharmacology*; D007700:Kinetics; D008177:Lupus Vulgaris / Q000209:etiology / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D016131:Lymphocyte Subsets / Q000737:chemistry / Q000187:drug effects; D053655:Receptors, Interleukin-21 / Q000032:analysis; D000098546:Interleukin-21
D016207:Cytokines; D007378:Interleukins; D053655:Receptors, Interleukin-21; D023201:CD40 Ligand; D000098546:Interleukin-21