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IL-21: an Executor of B Cell Fate Danijela Konforte, Nathalie Simard and Christopher J

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IL-21: an Executor of B Cell Fate Danijela Konforte, Nathalie Simard and Christopher J IL-21: An Executor of B Cell Fate Danijela Konforte, Nathalie Simard and Christopher J. Paige J Immunol 2009; 182:1781-1787; ; This information is current as doi: 10.4049/jimmunol.0803009 of September 25, 2021. http://www.jimmunol.org/content/182/4/1781 Downloaded from References This article cites 71 articles, 35 of which you can access for free at: http://www.jimmunol.org/content/182/4/1781.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 25, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. IL-21: An Executor of B Cell Fate1 Danijela Konforte,*‡ Nathalie Simard,*‡ and Christopher J. Paige2*†‡ IL-21 is a type I cytokine that shares the common recep- press similarly low levels of IL-21R (10). As T1 B cells mature to tor ␥-chain with IL-2, IL-4, IL-7, IL-9, and IL-15. B the T2 stage, the expression of IL-21R increases to levels com- cells are one of the lymphoid cell types whose develop- parable to that found on follicular B cells (10). IL-21R is also ment and function are regulated by IL-21. Depending present on human naive and germinal center (GC) B cells, but on the interplay with costimulatory signals and on the not on memory B cells and plasma cells (PCs) (11). The surface developmental stage of a B cell, IL-21 can induce pro- levels of IL-21R increase on murine naive B cells when they get liferation, differentiation into Ig-producing plasma activated either through the TLR or CD40, and on human memory B cells after stimulation through CD40 (9, 11). De- cells, or apoptosis in both mice and humans. Alone and Downloaded from in combination with Th cell-derived cytokines IL-21 velopment- and activation-dependent regulation of IL-21R ex- can regulate class switch recombination to IgG, IgA, or pression on the surface of B cells suggests that IL-21 has impor- IgE isotypes, indicating its important role in shaping the tant functions late in B cell development and in the immune effector function of B cells. This review highlights the response. role of IL-21 in B cell development, function, and dis- Like other ␥c-dependent cytokines, IL-21 activates the Janus ease and provides some perspectives on the future stud- family tyrosine kinases, Jak1 and Jak3, which, in turn, activate http://www.jimmunol.org/ ies in this area. The Journal of Immunology, 2009, 182: STAT1 and STAT3 and to a lesser extent STAT5. In vitro re- 1781–1787. sults obtained from activated murine splenocytes, EBV-in- fected human B cell lines, human chronic lymphocytic leuke- mia (CLL) B cells, and multiple myeloma lines indicate that terleukin-21 is a member of the family of common recep- IL-21:IL-21R binding leads to strong STAT3 activation (12– ␥ ␥ 3 tor -chain ( c) -dependent cytokines. Its structure is re- 15). In EBV-infected B cells, activated STAT3 is observed as I lated to the four-helix bundle type I cytokine and shows early as 5 min after binding and persists to up to 6 days (12). significant homology to IL-2, IL-4, and IL-15 (1). IL-21 was Activation of STAT1 is weaker, whereas activation of STAT5 is by guest on September 25, 2021 originally identified in the culture supernatants of activated hu- ϩ transient (Ͻ60 min) and is observed only in some cells, such as man CD3 T cells (1). Further studies established that Th17, T CLL B cells and activated murine splenocytes (12–14). Work- follicular helper (Tfh), and NKT cells also secrete IL-21 (2–5). ing with EBV-infected human B cell lines we found that inhi- IL-21 exerts pleiotropic actions on the immune system. Its bition of IL-21-induced JAK/STAT signaling did not interfere functional receptor, IL-21R, consisting of the IL-21R␣/␥c with the initial increase in proliferation of EBV-infected B cell complex, is expressed on various hematopoietic cells. The ef- lines. By contrast, intact JAK/STAT signaling was required for fects of IL-21 on T, NK, and dendritic cells (DCs) have been reviewed elsewhere and will not be discussed here (reviewed in the subsequent differentiation into late plasmablasts/early PCs (12). Biochemical studies of murine IL-21R␣ showed that si- Refs. 6–8). This review focuses on the influence of IL-21 in B ␣ cell biology. multaneous mutation of all six tyrosine residues in the IL-21R cytoplasmic domain greatly reduced IL-21-mediated prolifera- IL-21R expression and signaling tion of murine T cells, whereas retention of tyrosine 510 (Y510) In mice, the cell surface levels of IL-21R progressively increase only was sufficient for the full proliferative response. Y510 me- as B cells develop from progenitors in the bone marrow to ma- diated IL-21-induced activation of STAT1 and STAT3, but ture B cells in the peripheral lymphoid tissues (9). Transitional not STAT5, in T cells (14). The precise role of Y510 and the 1 (T1) B cells, which represent the most immature B cell pop- other tyrosine residues in IL-21R signaling in B cells has not yet ulation in the periphery, and marginal zone (MZ) B cells ex- been determined. Similarly, it is of interest to determine *Division of Stem Cell and Developmental Biology, Princess Margaret Hospital, Ontario 2 Address correspondence and reprint requests to Dr. Christopher J. Paige, Division of Cancer Institute, University Health Network, Toronto, Canada; and †Department of Stem Cell and Developmental Biology, Princess Margaret Hospital, Ontario Cancer In- Medical Biophysics and ‡Department of Immunology, University of Toronto, Toronto, stitute, No. 7-504, 610 University Avenue, Toronto, Ontario M5G 2M9. E-mail address: Canada [email protected] Received for publication November 17, 2008. Accepted for publication December 3 Abbreviations used in this paper: ␥c, common receptor ␥-chain; AID, activation-induced 24, 2008. cytidine deaminase; BAFF, B cell-activating factor (TNF family); CB, cord blood; CD40L, CD40 ligand; CSR, class switch recombination; CLL, chronic lymphocytic leukemia; DC, The costs of publication of this article were defrayed in part by the payment of page charges. dendritic cell; GC, germinal center; MZ, marginal zone; MZA, MZ analog; PB, peripheral This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. blood; PC, plasma cell; RA, rheumatoid arthritis; SHM, somatic hypermutation; SLE, Section 1734 solely to indicate this fact. systemic lupus erythematosus; Tfh, T follicular helper cell; WT, wild type. 1 This work was supported by the grants from the National Cancer Institute of Canada and by the Canadian Institutes of Health Research (CIHR) Grant 9862. N.S. is the recipient of Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 a graduate student scholarship from the CIHR. www.jimmunol.org/cgi/doi/10.4049/jimmunol.0803009 1782 BRIEF REVIEWS: IL-21 AND B CELLS whether certain IL-21R tyrosine residues can recruit phospha- and increase the cell death of murine follicular, MZ, and total tases or other proteins that inhibit STAT activation and help splenic B cells (9). In human in vitro systems, IL-2, IL-4, IL-10, terminate IL-21 signaling. and IL-13, known for their key roles in B cell function, had notably It will also be important to investigate whether the balance lower effects on proliferation of anti-CD40-stimulated B cells between IL-21-induced STAT1 and STAT3 signals influ- compared with IL-21 (11, 27, 28). Similarly as for murine B cells, ences different B cell fates. Generally, STAT1 has been im- anti-CD40 stimulation protected anti-IgM-activated human B plicated in cell cycle arrest and apoptotic cell death (16). By cells from IL-21-mediated death (27). contrast, STAT3 mostly functions as an antiapoptotic or The ability of IL-21 to induce apoptosis sets it apart from growth factor, especially in numerous malignancies where it other members of the ␥c-dependent family of cytokines, most is constitutively active (17–19). The consequence of STAT of which activate prosurvival and proliferation signals. Com- activation depends on the expression of STAT target genes plete protection from IL-21-mediated apoptosis was observed that are regulated directly or indirectly. Granzyme A, Jak3, when murine B cells were pretreated for 6 h with anti-CD40 Ab and IL-17R are among the genes activated by IL-21 in a and then cultured with IL-21 for 24 h. In this case, it was found STAT3-dependent fashion (20). We showed that intact that anti-CD40 induced gene and protein expression of a pro- JAK/STAT signal is required for IL-21-induced c-myc re- survival factor, Bcl-xL (29). IL-21-mediated apoptosis was not pression and subsequent differentiation of EBV-infected B blocked in FAS ligand or TNFRI- or TNFRII-transgenic mice, cell lines into late plasmablasts/early PCs (12). but it was blocked in Bcl-2 transgenic mice (9).
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