| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,
,
* Centenary Institute of Cancer Medicine and Cell Biology, New South Wales, Australia;
Faculty of Medicine, University of Sydney, New South Wales, Australia; and
Garvan Institute of Medical Research, New South Wales, Australia
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Health and Medical Research Council (NHMRC) of Australia and the Cancer Institute NSW. K.L.G. and V.L.B. are recipients of Postgraduate Research Awards from the University of Sydney. K.L.G. is the recipient of a Cancer Institute New South Wales Research Scholar Award. S.G.T. is the recipient of an R. D. Wright Career Development Award from the NHMRC of Australia.
2 Address correspondence and reprint requests to Dr. Stuart G. Tangye, Immunology and Inflammation Department, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst 2010, New South Wales, Australia. E-mail address: s.tangye{at}garvan.org.au
3 Abbreviations used in this paper: GC, germinal center, PC, plasma cell; SLE, systemic lupus erythematosus; TD, T dependent; TI, T independent; 
c, common chain; TFH, T follicular helper; CB, cord blood; ttfd, time-to-first division; MNC, mononuclear cell; SA, streptavidin; sq-PCR, semiquantitative PCR; rh, recombinant human; B-CLL, B-chronic lymphocytic leukemic; MFI, mean fluorescence intensity; PB, peripheral blood.
This article has been cited by other articles:
|
|
 |
|
  R. Spolski, H.-P. Kim, W. Zhu, D. E. Levy, and W. J. Leonard IL-21 Mediates Suppressive Effects via Its Induction of IL-10 J. Immunol., March 1, 2009; 182(5): 2859 - 2867. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Konforte, N. Simard, and C. J. Paige IL-21: An Executor of B Cell Fate J. Immunol., February 15, 2009; 182(4): 1781 - 1787. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Bubier, T. J. Sproule, O. Foreman, R. Spolski, D. J. Shaffer, H. C. Morse III, W. J. Leonard, and D. C. Roopenian A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice PNAS, February 3, 2009; 106(5): 1518 - 1523. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Good, D. T. Avery, and S. G. Tangye Resting Human Memory B Cells Are Intrinsically Programmed for Enhanced Survival and Responsiveness to Diverse Stimuli Compared to Naive B Cells J. Immunol., January 15, 2009; 182(2): 890 - 901. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R Ettinger, S Kuchen, and P E Lipsky Interleukin 21 as a target of intervention in autoimmune disease Ann Rheum Dis, December 1, 2008; 67(Suppl_3): iii83 - iii86. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Menoret, S. Maiga, G. Descamps, C. Pellat-Deceunynck, C. Fraslon, M. Cappellano, P. Moreau, R. Bataille, and M. Amiot IL-21 Stimulates Human Myeloma Cell Growth through an Autocrine IGF-1 Loop J. Immunol., November 15, 2008; 181(10): 6837 - 6842. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Lamprecht, S. Kreher, I. Anagnostopoulos, K. Johrens, G. Monteleone, F. Jundt, H. Stein, M. Janz, B. Dorken, and S. Mathas Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3{alpha} Blood, October 15, 2008; 112(8): 3339 - 3347. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Scholz, J. E. Crowley, M. M. Tomayko, N. Steinel, P. J. O'Neill, W. J. Quinn III, R. Goenka, J. P. Miller, Y. H. Cho, V. Long, et al. BLyS inhibition eliminates primary B cells but leaves natural and acquired humoral immunity intact PNAS, October 7, 2008; 105(40): 15517 - 15522. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Brune, E. Tiacci, I. Pfeil, C. Doring, S. Eckerle, C. J.M. van Noesel, W. Klapper, B. Falini, A. von Heydebreck, D. Metzler, et al. Origin and pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analysis J. Exp. Med., September 29, 2008; 205(10): 2251 - 2268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. T. Avery, C. S. Ma, V. L. Bryant, B. Santner-Nanan, R. Nanan, M. Wong, D. A. Fulcher, M. C. Cook, and S. G. Tangye STAT3 is required for IL-21-induced secretion of IgE from human naive B cells Blood, September 1, 2008; 112(5): 1784 - 1793. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. T. Avery, V. L. Bryant, C. S. Ma, R. de Waal Malefyt, and S. G. Tangye IL-21-Induced Isotype Switching to IgG and IgA by Human Naive B Cells Is Differentially Regulated by IL-4 J. Immunol., August 1, 2008; 181(3): 1767 - 1779. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Diehl, H. Schmidlin, M. Nagasawa, S. D. van Haren, M. J. Kwakkenbos, E. Yasuda, T. Beaumont, F. A. Scheeren, and H. Spits STAT3-Mediated Up-Regulation of BLIMP1 Is Coordinated with BCL6 Down-Regulation to Control Human Plasma Cell Differentiation J. Immunol., April 1, 2008; 180(7): 4805 - 4815. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. L. Bryant, C. S. Ma, D. T. Avery, Y. Li, K. L. Good, L. M. Corcoran, R. de Waal Malefyt, and S. G. Tangye Cytokine-Mediated Regulation of Human B Cell Differentiation into Ig-Secreting Cells: Predominant Role of IL-21 Produced by CXCR5+ T Follicular Helper Cells J. Immunol., December 15, 2007; 179(12): 8180 - 8190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kishida, Y. Hiromura, M. Shin-Ya, H. Asada, H. Kuriyama, M. Sugai, A. Shimizu, Y. Yokota, T. Hama, J. Imanishi, et al. IL-21 Induces Inhibitor of Differentiation 2 and Leads to Complete Abrogation of Anaphylaxis in Mice J. Immunol., December 15, 2007; 179(12): 8554 - 8561. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Hiromura, T. Kishida, H. Nakano, T. Hama, J. Imanishi, Y. Hisa, and O. Mazda IL-21 Administration into the Nostril Alleviates Murine Allergic Rhinitis J. Immunol., November 15, 2007; 179(10): 7157 - 7165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kuchen, R. Robbins, G. P. Sims, C. Sheng, T. M. Phillips, P. E. Lipsky, and R. Ettinger Essential Role of IL-21 in B Cell Activation, Expansion, and Plasma Cell Generation during CD4+ T Cell-B Cell Collaboration J. Immunol., November 1, 2007; 179(9): 5886 - 5896. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Anderson, M. M. Tomayko, A. Ahuja, A. M. Haberman, and M. J. Shlomchik New markers for murine memory B cells that define mutated and unmutated subsets J. Exp. Med., September 3, 2007; 204(9): 2103 - 2114. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Good and S. G. Tangye Decreased expression of Kruppel-like factors in memory B cells induces the rapid response typical of secondary antibody responses PNAS, August 14, 2007; 104(33): 13420 - 13425. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Tangye and K. L. Good Human IgM+CD27+ B Cells: Memory B Cells or "Memory" B Cells? J. Immunol., July 1, 2007; 179(1): 13 - 19. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
